The Biochemistry of Digestion, Absorption and Detoxification by Prof. Dr. Hedef D. El-Yassin (1)

Biochemistry of Digestion, Absorption and Detoxification 27/9-9/10/2011

1. 2. 3. 4. 5. 6.

Lecture 1: 1: Introduction to the Biochemistry of Digestion, absorption and detoxification. detoxification. Lecture 2 : Digestion and Digestive secretion from mouth and stomach Lecture 3: 3: Digestive secretion from pancreas and liver Lecture 4: 4: Detoxification in the liver Lecture 5 : Secretion and absorption in the small intestine Lecture 6 : Secretion and absorption in the large intestine

Aim and objective of the above six ect!"es is to !nde"stand: The biochemistry and mechanism of digestion of food 1 The abso absorpt rption ion of of basic basic nutri nutrient ents s ! The detox detoxific ificatio ation n mecha mechanis nism m

#efe"ences: 1. "Biochemistry" by #ubert Stryer

(textbook)

2. "Textboo$ of Biochemistry %ith &linical &orrelations" by T'Devlin (additional reading)

3. "#ippincott(s Illustrated )evie%s in i n Biochemistry" by *&&hampe, )A+arvey and D)errier (additional reading) 4. "+arper(s Biochemistry" by )-'urray, D-.ranner, *A 'ayes and /0)od%ell (additional reading)

Prof. Dr.H.D.El-Yassin1 2011

LECTURE 1

Tuesday 27/9/2011

Introduction to the Biochemistry of Digestion, Absorption and Detoxification Detoxification $nt"od!ction Digestion is the chemical brea$do%n of large food molecules into smaller molecules that can be used by b y cells The brea$do%n occurs %hen certain specific enymes are mixed %ith the food %n&'mes invoved in (i)estion *o'saccha"ides

matose

*"oteins

*e*tides

fats

fatt' acids and )'ce"o

)!cose

amino acids


LECTURE 1

Tuesday 27/9/2011

Review of Food Chemistry The diet of any animal contains hundreds if not thousands of different molecules, but the bul$ of the ingested nutrients are in the form of huge macromolecules that cannot be absorbed into blood %ithout first being reduced to much simpler and smaller forms The most important enymatic reaction in digestion of foodstuffs is hydrolysis 2 the brea$ing of a chemical bond by the addition of a %ater molecule Proteins *roteins are polymers of amino acids lin$ed together by peptide bonds &hain length varies tremendously and many dietary proteins have been modified after translation by addition of carbohydrate 3glycoproteins4 or lipid 3lipoprotein4 moieties /ery short proteins, typically 5 to 16 amino acids in length, are called peptides Lipids atty acids are present in only small amounts in animal and plant tissues, but are the building bloc$s of many important complex lipids True fatty acids possess a long hydrocarbon chain terminating t erminating in a carboxyl group 7early all fatty acids have an even number of carbons and have chains bet%een 18 and !! carbons in length The principle differences among the many fatty acids are the length of the chain 3usually 19 or 1 carbons4 and the positions of unsaturated or double bonds The most abundant storage form of fat in animals and plants, and hence the most important dietar dietary y lipid, is triglyceride A molecule of triglyceride is composed of a molecule of glycerol in %hich each of the three carbons is lin$ed through an ester bond to a fatty fatt y acid Triglycerides Triglycerides cannot be efficiently absorbed, and are enymatically digested by pancreatic lipase into a !2 monoglyceride and t%o free fatty acids, all of %hich can be absorbed ;ther lipases hydrolyse a triglyceride into glycerol and three fatty acids

LECTURE 1

Tuesday 27/9/2011


Carbohydrates 1 'onosaccharides or simple sugars are either hexoses 392carbon4 li$e glucose, galactose and fructose, or pentoses 3<2carbon4 li$e ribose These are the brea$do%n products of more complex carbohydrates and can be efficiently absorbed across the %all of the digestive tube and transported into blood ! Disaccharides are simply t%o monosaccharides lin$ed together by a glycosidic bond The disaccharides most important in nutrition and digestion are: • • • •

lactose or "mil$ sugar": glucose = galactose sucrose or "table sugar": glucose = fructose maltose: glucose = glucose ;ligosaccharides are relatively short chains of monosaccharides %hich typically are intermediates in the brea$do%n of polysaccharides to monosaccharides

5 *olysaccharides : •

•

•

Starch is a ma>or plant storage form of glucose It occurs in t%o forms: alpha2amylose, in %hich the glucoses are lin$ed together in straight chains, and amylopectin, in %hich the glucose chains are highly branched ?xcept for the branch points of amylopectin, the glucose monomers in starch are lin$ed via alpha312@84 glycosidic bonds, %hich, in the digestive tract of mammals, are hydrolyed by amylases &ellulose is the other ma>or plant carbohydrate It is the ma>or constituent of plant cell %alls, and more than half of the organic carbon on earth is found in cellulose &ellulose is composed on unbranched, linear chains of D2glucose molecules, lin$ed to one another by beta312 @84 glycosidic bonds, %hich no vertebrate has the capacity to enymatically digest .lycogen is the third large polymer of glucose and is the ma>or animal storage carbohydrate #i$e starch, the glucose molecules in glycogen are lin$ed together by alpha312@84 glycosidic bonds

LECTURE 1

Tuesday 27/9/2011


The process of digestion produces glucose, amino acids, glycerol, and fatty acids 3see above4 The energy in glucose is used to produce AT* via the reactions of glycolysis, cellular respiration, and the electron transport system 3see diagram belo%4 The body uses amino acids to construct proteins ?xcess amino acids can be used to synthesie pyruvate, acetyl &oA, and alpha $etogluterate, %hich enters the -rebs cycle .lycerol and fatty acids can be converted to pyruvate and Acetyl &oA and then enter cellular respiration

Mouth &he%ing brea$s food into smaller particles so that chemical digestion can occur faster • %n&'mes: Salivary amylase brea$s starch 3a polysaccharide4 do%n to maltose 3a disaccharide4 • Bicarbonate ions in saliva act as buffers, maintaining a p+ bet%een 9< and < • 'ucins 3mucous4 lubricate and help hold che%ed food together in a clump called a bolus


LECTURE 1

Tuesday 27/9/2011

Stomach The stomach stores up to ! liters of food .astric glands %ithin the stomach produce secretions called )ast"ic j!ice The muscular %alls of the stomach contract vigorously to mix food %ith gastric >uice, producing a mixture called chyme +ast"ic j!ice • Pepsio!e is converted to pepsin, %hich digests proteins *epsinogen production is stimulated by the presence of gastrin in the blood • "Cl +ydrochloric acid 3+&l4 converts pepsinogen to pepsi %hich brea$s do%n proteins to peptides +&l maintains a p+ in the stomach of approximately !6 It also dissolves food and $ills microorganisms #ucous protects the stomach from +&l and pepsin Secretio of $astric %uice& $astri is a hormone that stimulates the stomach to secrete gastric >uice

Duodenum The duodenum is the first part of the small intestine &hyme enters in tiny spurts At this point, proteins and carbohydrates are only partially digested and lipid digestion has not begun

Pancreas The pancreas acts as an exocrine gland by producing pacreatic 'uice %hich empties into the small intestine via a duct The pancreas also acts as an endocrine gland to produce insulin ,anc"eatic !ice *ancreatic >uice contains sodium bicarbonate %hich neutralies the acidic material from the stomach • Pacreatic amylase digests starch to maltose • (rypsi and Chymotrypsi digest proteins to peptides #i$e pepsin 3produced in the stomach4, they are specific for certain amino acids, not all of them They therefore produce peptides • Lipase digests fats to glycerol and fatty acids •


LECTURE 1

Tuesday 27/9/2011

Liver The liver produces )ile %hich is stored in !all)ladder and sent to the duodenum through a duct Bile emulsifies fats 3separates it into small droplets4 so they can mix %ith %ater and be acted upon by enymes the" !nctions of the ive" • The liver detoxifies blood from intestines that it receives via the hepatic portal vein • The liver stores glucose as glycogen 3animal starch4 and brea$s do%n glycogen to release glucose as needed This storage2release process maintains a constant glucose concentration in the blood 3614 If glycogen and glucose run short, proteins can be converted to glucose • It produces blood proteins • It destroys old red blood cells and converts hemoglobin from these cells to bilirubin and biliverdin %hich are components of bile • Ammonia produced by the digestion of proteins is converted to a less toxic compound 3urea4 by the liver

Hormones Involved in Digestion 1 +ast"in: The presence of food in the stomach stimulates specific receptors %hich in turn stimulates endocrine cells in the stomach to secrete the hormone !astri into the circulatory system .astrin stimulates the stomach to secrete gastric >uice ! ec"etin: Secretin is produced by cells of the duodenum ItCs production is stimulated by acid chyme from stomach It stimulates the pancreas to produce sodium bicarbonate, %hich neutralies the acidic chyme It also stimulates the liver to secrete bile 5  choec'stoinin: &&- production is stimulated by the presence of food in the duodenum It stimulates the gallbladder to release bile and the pancreas to produce pancreatic enymes 8 +$, +ast"ic $nhibito"' ,e*tide:ood in the duodenum stimulates certain endocrine cells to produce .I*


It has the opposite effects of gastrin it inhibits gastric glands in the stomach and it inhibits the mixing and churning movement of stomach muscles This slo%s the rate of stomach emptying %hen the duodenum contains food

LECTURE 1

Tuesday 27/9/2011

Small Intestine The small intestine is approximately 5 m long #i$e the stomach, it contains numerous ridges and furro%s In addition, there are numerous pro>ections called villi that that function to increase the surface area of the intestine Individual villus cells have microvilli %hich %hich greatly increase absorptive surface area The total absorptive surface area is eEuivalent to <66 or 966 sEuare meters ?ach villus contains blood vessels and a lacteal 3lymph 3lymph vessel4 *eptidases and maltase are embedded %ithin the plasma membrane of the microvilli ,e*tidases complete ,e*tidases complete the digestion of peptides to amino acids atase completes the digestion of disaccharides Abso"*tion:

The Large Intestine: It functions in three processes: • )ecovery of %ater and electrolytes from ingesta: ingesta: By the time ingesta reaches the terminal ileum, roughly F6 of its %ater has been absorbed, but considerable %ater and electrolytes li$e sodium and chloride remain and must be recovered by absorption in the large gut • ormation and storage of feces: feces: As ingesta is moved through the large intestine, it is dehydrated, mixed %ith bacteria and mucus, and formed into feces • 'icrobial fermentation: fermentation: The large intestine of all species teems %ith microbial life Those microbes produce enymes capable of digesting many of molecules that to vertebrates are indigestible, cellulose being a premier example Absorption: example Absorption: %ater, %ater, sodium ions and chloride ions Secretion: bicarbonate Secretion: bicarbonate ions and mucus •


LECTURE 1

Tuesday 27/9/2011

Summary of Digestive Enzymes 8he di)estive en&'mes in the tabe beo a"e s!mma"i&ed acco"din) to t'*e of food that the' di)est. ;;D TG*?

?7HG'?

S;)&?

*);D&TS

&A)B &A)B;+ ;+G GD)A D)AT?S

Sali Saliva vary ry amy amylase lase *ancreatic amylase 'altase

Salivary glands *ancreas Small intestine

'altose 'altose .lucose

*);T?I7S

*epsin Trypsin *eptidases

Stomach mucosa *eptides *ancreas *eptides Intestinal mucosa Amino acids

ATS

#ipase

*ancreas

atty acids and glycerol

8he tabe beo shos di)estive en&'mes )"o!*ed b' so!"ce of the en&'me. S;)&?

?7HG'?

;;D

*);D&T

';T+ 3salivary glands4

Salivary amylase

*olysaccharides

'altose

ST;'A&+

*epsin

*roteins

*eptides

*A7&)?AS

*ancreatic amylase Trypsin #ipase

*olysaccharides *roteins ats

'altose *eptides atty acids and glycerol

S'A## I7T?STI7?

'altase *eptidases

'altose *eptides

.lucose Amino acids


LECTURE 2

Thursday 29/9/2011

Digestion and Digestive Secretion from 'outh and Stomach The Mouth Coplex !ood substan"es taken by anials ust be broken do#n into siple$ soluble and di!!usible substan"es be!ore they "an be absorbed into the body. %n %n the outh outh$$ sali&ary glands se"rete glands se"rete *+ amylase,, #hi"h digests star"h into sall segents o! ultiple amylase sugars and sugars and into the indi&idual soluble sugars. 'ali&ary glands also glands also se"rete lysoye lysoye$$ #hi"h kills ba"teria ba"teria but but is not "lassi!ied as a digesti&e enye.

The 'toa"h oodstu!!s entering the stoa"h ha&e been$ "rushed and redu"ed in sie by asti"ation$ #ith sali&a. The stoa"h pro&ides four )asic fuctios that fuctios that assist in the early stages o! digestion and prepare the ingesta !or !urther pro"essing in the sall intestine* 1- %t ser&es as a short+term stora!e reservoir $ allo#ing a rather larg large e eal eal to be "onsued "onsued +ui"kly +ui"kly and and dealt #ith #ith o&er o&er an extended extended peri period od.. 2- %t is in the stoa"h that su)statial chemical ad e.ymatic di!estio is iitiated, particularly of proteis3- ,igorous "ontra"tions o! gastri" sooth us"le ix and grind !oods !oodstu tu!! !!s s #it #ith h gastri" gastr i" se"retio se "retions$ ns$ resulti r esulting ng in i n li/uefactio of food $ a prer pr ere+ e+ui uisi site te !or !or deli&e deli&ery ry o! o! the the inge ingesta sta to the the sal salll intestine. 4- -s !ood is li+ue!ied in the stoa"h$ it is slowly released ito the small itestie !or itestie !or !urther pro"essing. Prof. Dr.H.D.El-Yassin 10 2011

%! the lining o! the stoa"h is exained #ith a hand lens$ one "an see that it is "o&ered #ith nuerous sall holes. These are the openings o! gastri" pits #hi"h extend into the u"osa as straight and bran"hed tubules$ !oring gastri" glands. LECTURE 2

Thursday 29/9/2011

our aor types o! se"retory epithelial "ells "o&er the sur!a"e o! the stoa"h and extend do#n into gastri" pits and glands*

1. #ucous cells* se"rete an alkaline u"us that prote"ts the 2. epitheliu against shear stress and a"id 3. Parietal cells* se"rete hydro"hlori" a"id. 4. Chief cells* se"rete pepsin$ a proteolyti" enye /. $ cells* se"rete the horone gastrin Prof. Dr.H.D.El-Yassin 11 2011

LECTURE 2

Thursday 29/9/2011

$astric secretios 1. Mucosal Protection Mu"us layer on gastri" sur!a"e !ors a u"osal barrier to daage against se&eral !ors o! potential inury to the gastri" u"osa. 1. - gel 0.2 thi"k 0 C5 20 protein 2. 'e"reted by ne"k "ells$ sur!a"e epitheliu 3. Can be "lea&ed by pepsin$ so "ontinual produ"tion is re+uired 4. 6elease is stiulated by a"etyl"holine !ro ner&e endings /. -lso ri"h in bi"arbonate a. C537 "ontent "reates a 8i"ro7en&ironent8 around sur!a"e "ells to pre&ent a"id daage b. C537 se"retion is inhibited by adrenergi" input (proinent in stress)

2. Acid Secretion ydro"hlori" a"id is se"reted !ro parietal "ells into the luen #here it establishes an extreely a"idi" en&ironent. This a"id is iportant !or a"ti&ation o! pepsinogen and ina"ti&ation o! ingested i"roorganiss su"h as ba"teria. 2-1- Fuctio of $astric acid 1.

To kill i"ro7organiss* (but . pylori sur&i&es by aking aonia (basi") !ro urea using urease).

2. to pro&ide the optial p !or pepsin a"tion 3. to a"ti&ate pepsinogens ("lea&ed to !or pepsin) 4. a"ilitating absorption o! iron by "on&erting "olloidal iron into ioni" !or. Prof. Dr.H.D.El-Yassin 12 2011

/. stiulating duodenu to liberate se"retin 9. breaks do#n "onne"ti&e tissue in !ood

LECTURE 2

Thursday 29/9/2011

2-2-#echaism of !astric acid secretio The hydrogen ion "on"entration in parietal "ell se"retions is roughly 3 illion !old higher than in blood$ C1 at a "on"entration o! roughly 190 M (e+ui&alent to a p o! 0.). -nd "hloride is se"reted against both a "on"entration and ele"tri" gradient. Thus$ the ability o! the parietal "ell to se"rete a"id is dependent on a"ti&e transport. -"id se"retion e"haniss in the parietal "ell

Prof. Dr.H.D.El-Yassin 13 2011

The key player in a"id se"retion is a :;<: -TPase or 8proton pup8 lo"ated in the "annali"ular ebrane. This -TPase is agnesiu7 dependent.

LECTURE 2

Thursday 29/9/2011

(he " 0  0 (Pase The parietal "ells in the stoa"h use this pup to se"rete gastri" ui"e. These "ells transport protons ( : ) !ro a "on"entration o! about 4 x 10 7 M #ithin the "ell to a "on"entration o! about 0.1/ M in the gastri" ui"e (gi&ing it a p "lose to 1). 'all #onder that parietal "ells are stu!!ed #ith ito"hondria and uses huge aounts o! energy as they "arry out this three7illion !old "on"entration o! protons. The "urrent odel !or explaining a"id se"retion is as !ollo#s* = ydrogen ions are generated #ithin the parietal "ell !ro disso"iation o! #ater. The hydroxyl ions !ored in this pro"ess rapidly "obine #ith "arbon dioxide to !or bi"arbonate ion$ a rea"tion "atayled by "arboni" anhydrase. = >i"arbonate is transported out o! the basolateral ebrane in ex"hange !or "hloride. The out!lo# o! bi"arbonate into blood results in a slight ele&ation o! blood p kno#n as the 8alkaline tide8. This pro"ess ser&es to aintain intra"ellular p in the parietal "ell. = Chloride and potassiu ions are transported into the luen o! the "annali"ulus by "ondu"tan"e "hannels$ and su"h is ne"essary !or se"retion o! a"id.


= ydrogen ion is puped out o! the "ell$ into the luen$ in ex"hange !or potassiu through the a"tion o! the proton pup potassiu is thus e!!e"ti&ely re"y"led. -""uulation o! osoti"ally7a"ti&e hydrogen ion in the "annali"ulus generates an osoti" gradient a"ross the ebrane that results in out#ard di!!usion o! #ater 7 the resulting gastri" ui"e is 1// M C1 and 1/ M
Thursday 29/9/2011

2-3- Cotrol of !astric acid secretio Parietal "ells bear re"eptors !or three stiulators o! a"id se"retion$ re!le"ting a neural$ para"rine and endo"rine "ontrol* •

-C@TALC5L%?@ released !ro "holinergi" ner&e !ibres o binds to (M3) re"eptor on "ell sur!a"e :: o opens Ca "hannels in api"al sur!a"e :: !ro intra"ellular stores o prootes release o! Ca o

•

B-'T6%? o o

•

binds to CC<7> re"eptor on "ell sur!a"e releases intra"ellular Ca::

4%'T-M%?@

released !ro ast "ells o binds to parietal "ell sur!a"e re"eptor o a"ti&ates adenyl "y"lase (in"reases "y"li" -MP$ an intra"ellular essenger) o


LECTURE 2

Thursday 29/9/2011

istaines e!!e"t on the parietal "ell is to a"ti&ate adenylate "y"lase$ leading to ele&ation o! intra"ellular "y"li" -MP "on"entrations and a"ti&ation o! protein kinase - (P<-). 5ne e!!e"t o! P<- a"ti&ation is phosphorylation o! "ytoskeletal proteins in&ol&ed in transport o! the :;<: -TPase !ro "ytoplas to plasa ebrane. >inding o! a"etyl"holine and gastrin both result in ele&ation o! intra"ellular "al"iu "on"entrations. %?%>%T56A C5?T65L = a"id at less than p 2 is a dire"t inhibitor o! a"id release = a"id in duodenu releases se"retin #hi"h inhibits gastri" se"retion = !atty a"ids$ peptides stiulate release o! B% (gastri" inhibitory polypeptide) and CC< ("hole"ystokinin) 'e&eral additional ediators ha&e been sho#n to result in gastri" a"id se"retion #hen in!used into anials and people$ in"luding e.g. "al"iu. Cal"iu siulates gastrin release. lt is un"lear #hether these ole"ules ha&e a signi!i"ant physiologi" role in parietal "ell !un"tion. Prof. Dr.H.D.El-Yassin 16 2011

-lkaline tide during gastri" se"retion* 5#ing to se"reation o! a lage aount o!  : as Cl$ there is surplus o! 5 7 in the parietal "ell #hi"h is taken up not only by the C5 2 to !or C5 37 but also by other bu!!er systes o! parietal "ell initially and later by those o! plasa. 2

−

HPO4

−

H 2 PO4

−

HCO 3

Lactate

H 2 CO 3

Lactic acid

-ll tend to in"rease on the side o! the base i.e.*P5472 $ C537 and la"tate$ #ith the result that the p o! plasa is raised and an alkaline urine is ex"reted !or soe hours !ollo#ing intake o! !ood and gastri" se"retion. This is kno#n as the alkaline tide.


LECTURE 2

Thursday 29/9/2011

3. Proteases: Pepsinogen$ an inactive ymogen, is secreted into gastric >uice from both mucous cells and chief cells ;nce secreted, pepsinogen is activated by stomach acid into the a"ti&e protease pepsin$ %hich is largely responsible for the stomach(s ability to initiate digestion of proteins, in young animals chief cells also secrete "hyosin (rennin)$ a protease that coagulates mil$ protein allo%ing it to be retained more than briefly in the stomach Pepsinogens and Pepsins *epsinogens are secreted in a form such that the activation peptide assumes a compact structure that occludes the active site ;n exposure to an acidic 3p+ J 84 environment such as occurs in the lumen of the stomach, the activation peptide unfolds, allo%ing the active site to clip it off, yielding mature, catalytically active pepsin ;ptimal activity of pepsins is at p+ of 1 to 5<, depending on the isoform, They are reversibly inactivated at about p+ < and irreversibly inactivated at p+  to  The mature, active enymes are roughly 325 amino acids %ith a mass of approximately 35 (a *epsin initiates protein digestion by splitting certain amino acid lin$ages in proteins 3&leaves preferentially &2terminal It does not cleave at /, A or . ;ther residues may be cleaved, %ith very variable rates4 to yield peptide fragments

Prof. Dr. Hedef Dhar El-Yassin 2011 18

LECTURE 2

Thursday 29/9/2011

Because pepsin can digest protein, it must be stored and secreted in an inactive form so that it does not digest the cells in %hich it is formed %n general$ se"retion o! pepsinogens is "oupled to se"retion o! a"id !ro the parietal "ell. %n &itro studies ha&e deonstrated that se"retion is e!!e"ti&ely stiulated by agents that stiulate either o! t#o "onditions* 1 @le&ated intra"ellular le&els o! "y"li" -MP* exaples in"lude se"retin$ &asoa"ti&e intestinal peptide and epinephrine. ! @le&ated intra"ellular "al"iu* the prin"ipal ediators in&estigated in"lude a"etyl"holine and peptides o! the gastrin;"hole"ystokinin !aily Pepsin #as dis"o&ered by Theodor '"h#ann in 139. %t #as the !irst anial enye to be dis"o&ered. Chyosin (6ennin) and the Coagulation o! Milk Chyosin$ kno#n also as rennin$ is a proteolyti" enye synthesied by "hie! "ells in the stoa"h. %ts role in digestion is to "oagulate ilk in the stoa"h$ a pro"ess o! "onsiderable iportan"e in the &ery young anial. %! ilk #ere not "oagulated$ it #ould rapidly !lo# through the stoa"h and iss the opportunity !or initial digestion o! its proteins. Chyosin e!!i"iently "on&erts li+uid ilk to a seisolid like "ottage "heese$ allo#ing it to be retained !or longer periods in the stoa"h. Chyosin se"retion is axial during the !irst !e# days a!ter birth$ and de"lines therea!ter$ repla"ed in e!!e"t by se"retion o! pepsin as the aor gastri" protease. Prof. Dr. Hedef Dhar El-Yassin 2011 19

LECTURE 2

Thursday 29/9/2011

Chyosin is se"reted as an ina"ti&e proenye "alled pro"hyosin that$ like pepsin$ is a"ti&ated on exposure to a"id. Chyosin is also siilar to pepsin in being ost a"ti&e in a"idi" en&ironents$ #hi"h akes sense "onsidering its ission. -side !ro its physiologi" role$ "hyosin is also a &ery iportant industrial enye be"ause it is #idely used in "heese aking.

4. Hormones The prin"iple horone se"reted !ro the gastri" epitheliu is gastrin$ a peptide that is iportant in "ontrol o! a"id se"retion and gastri" otility. Bastrin is se"reted by B7"ells and released into the blood #here it tra&els to the parietal "ells to stiulate a"id se"retion$ and to @ntero"hroa!!in7Like (@CL) Cells to stiulate histaine se"retion. The net result o! gastrin se"retion is in"reased a"id produ"tion through t#o e"haniss* 1. Dire"t stiulation o! the parietal "ells$ 2. Tropi" a"tion on parietal "ells in"reasing their nuber. ?.>. in gastrinoa (Eollinger7@llison syndroe) in"reased produ"tion o! gastrin "auses hyperse"retion o! a"id #hi"h is not sube"t to noral inhibitory e"haniss. A number of other enymes are secreted by gastric epithelial cells, including a lipase and gelatinase ;ne secretory product of considerable importance in man is intrinsic factor, a glycoprotein secreted by parietal cells that is necessary for intestinal absorption of vitamin B1!


LECTURE 2

Thursday 29/9/2011

Intrinsic actor %ntrinsi" !a"tor is a gly"oprotein se"reted by parietal (huans) o! the gastri" u"osa. %n huans$ it has an iportant role in the absorption o! &itain B1! ("obalain) in the intestine$ and !ailure to produ"e or utilie intrinsi" !a"tor results in the "ondition perni"ious aneia.F as a result o! an autoiune atta"k against parietal "ells F Dietary &itain B1! is released !ro ingested proteins in the stoa"h through the a"tion o! pepsin and a"id. %t is rapidly bound by one o! t#o &itain B1!7binding proteins that are present in gastri" ui"e at a"id p$ these binding proteins ha&e a greater a!!inity !or the &itain than does intrinsi" !a"tor. %n the sall intestine pan"reati" proteases digest the binding proteins$ releasing &itain B1! #hi"h then be"oes bound to intrinsi" !a"tor. inally$ there are re"eptors !or intrinsi" !a"tor on the ileal u"osa #hi"h bind the "oplex$ allo#ing &itain B1! to be absorbed into portal blood. %n all aals$ &itain B1!is ne"essary !or aturation o! erythro"ytes$ and a de!i"ien"y o! this &itain leads to de&elopent o! aneia. 'in"e e!!i"ient absorption o! &itain B1!in huans depends on intrinsi" !a"tor$ diseases #hi"h de"rease the se"retion o! intrinsi" !a"tor (e.g. atrophi" gastritis)$ inter!ere #ith "lea&age o! the binding proteins (e.g. pan"reati" exo"rine insu!!i"ien"y) or de"rease binding and absorption o! the intrinsi" !a"tor7&itain >12 "oplex (e.g. ileal disease or rese"tion) "an result in this type o! aneia. Abso"*tion in the tomach The stoa"h absorbs &ery !e# substan"es$ although sall aounts o! "ertain lipid7soluble "opounds "an be taken up$ in"luding aspirin$ other non7steroidal anti7in!laatory drugs$ and ethanol. ?otably$ these substan"es are also #ell7re"ognied "auses o! gastri" irritation and their use (espe"ially o&eruse) is "oonly asso"iated #ith de&elopent o! gastritis and gastri" ul"ers.


LECTURE 3

Sunday 2/10/2011

Dies!i"e Se#re!i$n %r$& 'an#reas and Li"er

The pancreas plays a vital role in accomplishing the follo%ings: K Acid must be Euic$ly and efficiently neutralied to prevent damage to the duodenal mucosa K 'acromolecular nutrients 2 proteins, fats and starch 2 must be bro$en do%n much further before their constituents can be absorbed through the mucosa into blood Insufficient exocrine secretion by the pancreas leads to starvation, even if the body is consuming adeEuate Euantities of high Euality food In addition to its role as an exocrine organ, the pancreas is also an endocrine organ The ma>or hormones it secretes 2 insulin and glucagon 2 play a vital role in carbohydrate and lipid metabolism

%xoc"ine ec"etions of the ,anc"eas Prof. Dr. Hedef Dhar El-Yassin 2011 22

LECTURE 3

Sunday 2/10/2011

*ancreatic >uice is composed of t%o secretory products critical to proper digestion: digestive enymes and bicarbonate The enymes are synthesied and secreted from the exocrine acinar cells, %hereas bicarbonate is secreted from the epithelial cells lining small pancreatic ducts 1. (i)estive %n&'mes: a- Proteases Digestion of proteins is initiated by pepsin in the stomach, but the bul$ of protein digestion is due to the pancreatic proteases Several proteases are synthesied in the pancreas and secreted into the lumen of the small intestine The t%o ma>or

pancreatic

proteases

are

trypsin

and

chymotrypsin

both

are

endopeptidases, %hich are synthesied and pac$aged into secretory vesicles as the inactive proenymes trypsinogen and chymotrypsinogen (rypsi: &leaves peptide bonds on the &2terminal side of arginines and lysines Chymotrypsi: &uts on the &2terminal side of tyrosine, phenylalanine, and tryptophan residues 3the same bonds as pepsin, %hose action ceases %hen the 7a+&;s raises the p+ of the intestinal contents4


LECTURE 3

Sunday 2/10/2011

;nce trypsinogen and chymotrypsinogen are released into the lumen of the small intestine, they must be converted into their active forms in order to digest proteins, Trypsinogen is activated by the enyme entero$inase, %hich is embedded in the intestinal mucosa ;nce trypsin is formed, it activates chymotrypsinogen, as %ell as additional molecules of trypsinogen The net result is a rather explosive appearance of active protease once the pancreatic secretions reach the small intestine

Trypsin and chymotrypsin digest proteins into peptides and peptides into smaller peptides, but they cannot digest proteins and peptides t o single amino acids Some of the other proteases from the pancreas, for instance car)o4ypeptidase 3exopeptidase4 3This en1yme removes, one by one, the amino acids at the &2terminal of peptides4 But the final digestion of peptides into amino acids is largely the effect of peptidases in small intestinal epithelial cells


LECTURE 3

Sunday 2/10/2011

)- Pan"reati" Lipase The ma>or form of dietary fat is triglyceride, or neutral lipid A triglyceride molecule cannot be directly absorbed across the intestinal mucosa It must first be digested into a !2monoglyceride and t%o free fatty acids The enyme that performs this hydrolysis is pancreatic lipase Sufficient Euantities of bile salts must also be present in the lumen of the intestine in order for lipase to efficiently digest dietary triglyceride and for the resulting fatty acids and monoglyceride to be absorbed This means that normal digestion and absorption of dietary fat is critically dependent on secretions from both the pancreas and liver *ancreatic lipase has recently been in the limelight as a target for management of obesity The drug orlistat 3Lenical4 is a pancreatic lipase inhibitor that interferes %ith digestion of triglyceride and thereby reduces absorption of dietary fat &linical trials support the contention that inhibiting lipase can lead to significant reductions in body %eight in some patients c- -ylase The ma>or dietary carbohydrate for many species is starch, a storage form of glucose in plants Amylase is the enyme that hydrolyses starch to maltose 3a glucose2glucose disaccharide4, as %ell as the trisaccharide maltotriose and small branchpoints fragments called dextrins d- 5ther Pan"reati" @nyes In addition to the proteases, lipase and amylase, the pancreas produces a host of other digestive enymes, including nucleases, gelatinase and elastase •

!ceases These hydrolye ingested nucleic acids 3)7A and D7A4 into their component nucleotides


•

%astase: &uts peptide bonds next to small, uncharged side chains such as those of alanine and serine

LECTURE 3

Sunday 2/10/2011

2. ;ica"bonate and uice

&ontrol of *ancreatic ?xocrine Secretion Secretion from the exocrine pancreas is regulated by both neural and endocrine controls During interdigestive periods, very little secretion ta$es place, but as food enters the stomach and, a little later, chyme flo%s into the small intestine, pancreatic secretion is strongly stimulated Prof. Dr. Hedef Dhar El-Yassin 2011 26

LECTURE 3

Sunday 2/10/2011

The most important stimuli for pancreatic secretion come from three hormones secreted by the enteric endocrine system: K hoec'stoinin: This hormone is synthesied and secreted by enteric endocrine cells located in the duodenum Its secretion is strongly stimulated by the presence of partially digested proteins and fats in the small intestine As chyme floods into the small intestine, cholecysto$inin is released into blood and binds to receptors on pancreatic acinar cells, ordering them to secrete large Euantities of digestive enymes It also stimulates the gallbladder to release bile and the pancreas to produce pancreatic enymes

K

ec"etin: This hormone is secreted in response to acid in the duodenum The predominant effect of secretin on the pancreas is to stimulate duct cells to secrete %ater and bicarbonate As soon as this occurs, the enymes secreted by the acinar cells are flushed out of the pancreas, through the pancreatic duct into the duodenum It also stimulates the liver to secrete bile

K

+ast"in: This hormone, %hich is very similar to cholecysto$inin, is secreted in large amounts by the stomach in response to gastric distention and irritation, in addition to stimulating acid secretion by the parietal cell gastrin stimulates pancreatic acinar cells to secrete digestive enymes


LECTURE 3

Sunday 2/10/2011

The Liver The liver is the largest gland in the body and performs an astonishingly large number of tas$s that impact all body systems ;ne conseEuence of this complexity is that hepatic disease has %idespread effects on virtually all other organ systems The three fundamental roles of the liver are: 1 /ascular functions: including formation of lymph and hepatic phagocytic system ! 'etabolic achievements in control of synthesis and utiliation of carbohydrates, lipids and proteins 5 Secretory and excretory functions, particularly %ith respect to the synthesis of secretion of bile The latter is the only one of the three that directly affects digestion 2 the liver, through its biliary tract, secretes bile acids into the small intestine %here they assume a critical role in the digestion and absorption of dietary lipids



LECTURE 3

Sunday 2/10/2011

Secretion of Bile and the )ole of Bile Acids in Digestion Bile is a complex fluid containing %ater, electrolytes and a battery of organic molecules including bile acids, cholesterol, phospholipids and bilirubin that flo%s through the biliary tract into the small intestine There are t%o fundamentally important functions of bile in all species: •

;ie contains bie acids= hich a"e c"itica fo" di)estion and abso"*tion of fats and fat-so!be vitamins in the sma intestine.

•

an' aste *"od!cts a"e eiminated f"om the bod' b' sec"etion into bie and eimination in feces.

The secretion of bile can be considered to occur in t%o stages: K

Initially, hepatocytes secrete bile into canaliculi, from %hich it flo%s into bile ducts This hepatic bile contains large Euantities of bile acids, cholesterol and other organic molecules

K As bile flo%s through the bile ducts it is modified by addition of a %atery, bicarbonate2rich secretion from ductal epithelial cells

In humans: the gall bladder stores and concentrates bile during the fasting state Typically, bile is concentrated five2fold in the gall bladder by absorption of %ater and small electrolytes 2 virtually all of the organic molecules are retained Secretion into bile is a ma>or route for eliminating cholesterol ree cholesterol is virtually insoluble in aEueous solutions, but in bile, it is made soluble by bile acids and lipids li$e lethicin .allstones 3&holelithiasis4 most of %hich are composed predominantly of cholesterol, result from processes that allo% cholesterol to precipitate from solution in bile

LECTURE 3

Sunday 2/10/2011

)ole of Bile Acids in at Digestion and Absorption Bile salts are formed in the hepatocytes by a series of enymatic steps that convert cholesterol to cholic or chenodeoxycholic acids The rate limiting step is hydroxylation at the 2alpha position These reactions include the activity of  enymes belonging to either monooxygenase or dehydrogenase enyme classes

There are four ma>or bile acids found in the body:

1 &holic acid ! Deoxycholic acid 5 Decholin 8 &henodiol 3&henix4, is used to dissolve gallstones in patients %ho cannot tolerate surgery &henodiol is a natural bile acid that bloc$s production of cholesterol  This action leads to gradual dissolution of cholesterol gallstones

LECTURE 3

Sunday 2/10/2011

Synthesis of bile acids is one of the predominant mechanisms for the excretion of excess cholesterol +o%ever, the excretion of cholesterol in the form of bile acids is insufficient to compensate for an excess dietary inta$e of cholesterol These acids are then con>ugated %ith glycine or taurine and secreted as 7a= 3or -=4 salts &on>ugation causes a decrease in their p-a values, ma$ing them more %ater soluble

The most abundant bile acids in human bile are chenodeoxycholic acid 38<4 and cholic acid 3514 These are referred to as the primary bile acids 0ithin the intestines the primary bile acids are acted upon by bacteria and converted to the secondary bile acids, identified as deoxycholate 3from cholate4 and lithocholate 3from chenodeoxycholate4 Both primary and secondary bile acids are reabsorbed by the intestines and delivered bac$ to the liver via the portal circulation 0ithin the liver the carboxyl group of primary and secondary bile acids is con>ugated via an amide bond to either glycine or taurine before their being resecreted into the bile canaliculi These con>ugation reactions yield glycocon>ugates and taurocon>ugates, respectively The bile canaliculi >oin %ith the bile ductless, %hich then form the bile ducts Bile acids are carried from the liver through these ducts to the gallbladder, %here they are stored for future use The ultimate fate of bile acids is secretion into the intestine, %here they aid in the emulsification of dietary lipids In the gut the glycine and taurine residues are removed and the bile acids are either excreted 3only a small percentage4 or reabsorbed by the gut and returned to the liver This process of secretion from the liver to the gallbladder, to the intestines and finally reabsorbtion is termed the enterohepati" "ir"ulation.

LECTURE 3

Sunday 2/10/2011

?nterohepatic )ecirculation After the bile acids has been released into the small intestine via the bile duct to play an integral role in the absorption of dietary lipids and lipid soluble vitamins 'ore than F6 of the bile salts are actively reabsorbed 3by a sodium2dependent co2 transport process4 from the ileum into the hepatic2portal circulation from %here they are cleared and resecreted by the liver to once again be stored in the gall bladder This secretionMreabsorption cycle is called the ?nterohepatic &irculation

Systemic circulatio: supplies nourishment to all of the tissue located throughout your body, %ith the exception of the heart and lungs because they have their o%n systems Systemic circulation is a ma>or part of the overall circulatory system Portal circulatio: Blood from the gut and spleen flo% to and through the liver before returning to the right side of the heart This is called the portal circulation and the large vein through %hich blood is brought to the liver is called the portal vein The net effect of this enterohepatic recirculation is that each bile salt molecule is reused about !6 times, often t%o or three times during a single digestive phase

LECTURE 3

Sunday 2/10/2011

7ote: liver disease can dramatically alter this pattern of recirculation 2 for instance, sic$ hepatocytes have decreased ability to extract bile acids from portal blood and damage to the canalicular system can result in escape of bile acids into the systemic circulation Assay of systemic levels of bile acids is used clinically as a sensitive indicator of hepatic disease

Bile acids are facial amphipathic, that is, they contain both hydrophobic 3lipid soluble4 and polar 3hydrophilic4 faces The cholesterol2derived portion of a bile acid has one face that is hydrophobic 3that %ith methyl groups4 and one that is hydrophilic 3that %ith the hydroxyl groups4 the amino acid con>ugate is polar and hydrophilic Their amphipathic nature enables bile acids to carry out t%o important functions: 1 ?mulsification of lipid aggregates: Bile acids have detergent action on particles of dietary fat, %hich causes fat globules to brea$ do%n or be emulsified into minute, microscopic droplets ?mulsification is not digestion per se, but is of importance because it greatly increases the surface area of fat, ma$ing it available for digestion by lipases, %hich cannot access the inside of lipid droplets ! Solubiliation and transport of lipids in an aEueous environment: Bile acids are lipid carriers and are able to solubilie many lipids by forming micelles 2 aggregates of lipids such as fatty acids, cholesterol and monoglycerides 2 that remain suspended in %ater Bile acids are also critical for transport and absorption of the fat2soluble vitamins

S$(u)i(i!y *r$*er!ies $% )i(e a#ids in a+ue$us s$(u!i$ns. ,))re"ia!i$n- CC #ri!i#a( &i#e((ar #$n#en!ra!i$n

34

Prof.Dr H.D.El-Yassin 2011

LECTURE 3

Sunday 2/10/2011

Clini"al 'igni!i"an"e o! >ile -"id 'ynthesis Bile acids perform four physiologically significant functions: 1 Their synthesis and subseEuent excretion in the feces represent the only significant mechanism for the elimination of excess cholesterol ! Bile acids and phospholipids solubilie cholesterol in the bile, thereby preventing the precipitation of cholesterol in the gallbladder 5 They facilitate the digestion of dietary triacylglycerols by acting as emulsifying agents that render fats accessible to pancreatic lipases 8 They facilitate the intestinal absorption of fat2soluble vitamins )ole of Bile Acids in &holesterol +omeostasis +epatic synthesis of bile acids accounts for the ma>ority of cholesterol brea$do%n in the body In humans, roughly <66 mg of cholesterol are converted to bile acids and eliminated in bile every day This route for elimination of excess cholesterol is probably important in all animals, but particularly in situations of massive cholesterol ingestion Interestingly, it has recently been demonstrated that bile acids participate in cholesterol metabolism by functioning as hormones that alter the transcription of the rate2limiting enyme in cholesterol biosynthesis *attern and &ontrol of Bile Secretion The flo% of bile is lo%est during fasting, and a ma>ority of that is diverted into the gallbladder for concentration 0hen chyme from an ingested meal enters the small intestine, acid and partially digested fats and proteins stimulate secretion of cholecysto$inin and secretin These enteric hormones have important effects on pancreatic exocrine secretion They are both also important for secretion and flo% of bile:

35


LECTURE 3

Sunday 2/10/2011

1 &holecysto$inin: The name of this hormone describes its effect on the biliary system 2 cholecysto N gallbladder and $inin N movement The most potent stimulus for release of cholecysto$inin is the presence of fat in the duodenum ;nce released, it stimulates contractions of the gallbladder and common bile duct, resulting in delivery of bile into the gut ! Secretin: This hormone is secreted in response to acid in the duodenum Its effect on the biliary system is very similar to %hat %as seen in the pancreas 2 it simulates biliary duct cells to secrete bicarbonate and %ater, %hich expands the volume of bile and increases its flo% out into the intestine

36


LECTURE 4

Tuesday 4/10/2011

Detoxication in t!e "i#er The liver is one of the most important organs in the body %hen it comes to detoxifying or getting rid of foreign substances or toxins, especially from the gut The liver detoxifies harmful substances by a complex series of chemical reactions The role of these various enyme activities in the liver is to convert !at soluble toxins into #ater soluble substances that can be excreted in the urine or the bile depending on the particular characteristics of the end product 'any of the toxic chemicals that enter the body are fat2 soluble, %hich means they dissolve only in fatty or oily solutions and not in %ater This ma$es them difficult for the body to excrete at soluble chemicals have a high affinity for fat tissues and cell membranes, %hich are composed of fatty acids and proteins In these fatty tissues of the body, toxins may be stored for years, being released during times of exercise, stress or fasting

The liver plays several roles in detoxification: it filters the blood to remove large toxins, synthesies and secretes bile full of cholesterol and other fat2 soluble toxins, and enymatically disassembles un%anted chemicals LECTURE 4

Tuesday 4/10/2011

37


LECTURE 4

Tuesday 4/10/2011

This enymatic process usually occurs in t%o steps referred to as: • •

phase % and phase %% 

*hase I either directly neutralies a toxin, or modifies the toxic chemical to form activated intermediates %hich are then neutralied by one of more of the several phase II enyme systems

The level of exposure to environmental carcinogens varies %idely, as does the efficiency of the detoxification enymes, particularly phase II +igh levels of exposure to carcinogens coupled %ith slo% detoxification enymes significantly increases susceptibility to cancer

38


LECTURE 4

Tuesday 4/10/2011

,hase $ (etoxification This path%ay converts a toxic chemical into a less harmful chemical This is achieved by various chemical reactions 3such as oxidation, reduction and hydrolysis4, and during this process free radicals are produced %hich, if excessive, can damage the liver cells Antioxidants reduce the damage caused by these free radicals If antioxidants are lac$ing and toxin exposure is high, toxic chemicals become far more dangerous Some may be converted from relatively harmless substances into potentially carcinogenic substances The effects of exposure to toxins varies from individual to individual Some people are highly sensitive to different endogenous and exogenous toxins ;thers, because their bodies are more resilient and their livers can detoxify more efficiently, aren(t as sensitive  >8?#% ,450 ,450 @>+%A%   >8% 'onooxygenase 3mixed function oxidases4 incorporate one atom from molecular oxygen into a substrate 3creating a hydroxyl group4, %ith the other atom being reduced to %ater In the "yto"hroe P4/0 onooxygenase syste 7AD*+ provides the reducing eEuivalents reEuired by the series of reactions This system performs different functions in t%o separate locations in cellsThe overall reaction catalyed by a "yto"hroe P4/0 enye is:

#-?  2  A(,?  ? 

#-?  ?2  A(, 

%here ) may be a steroid, drug or other chemical 1 #itochodrial System: the function of the mitochondrial "yto"hroe P4/0 onooxygenase syste is to participate in the hydroxylation of steroids, a process that ma$es theses hydrophobic compounds more %ater soluble or example, in the steroid hormone producing tissues, such as placenta, ovaries, testes and adrenal cortex, it is used to hydroxylate intermediates in the conversion of cholesterol to steroid hormones The liver uses this system in bile acid synthesis, and $idney uses it to hydroxylat vitamin !<2hydroxycholecalciferol 3vitamin D4 to its biologically active 1, !<2hydroxylated form

39


LECTURE 4

Tuesday 4/10/2011

! #icrosomal System: An extremely important function the function of the microsomal "yto"hroe P4/0 onooxygenase syste found associated %ith the membranes of the endoplasmic reticulum 3particularly in the liver4 is the detoxification of foreign compounds 3xenobiotics4 Theses include numerous drugs such as varied pollutants as petroleum products, carcinogens and pesticides The "yto"hroe P4/0 onooxygenase syste can be used to hydroxylate theses toxins again using 7AD*+ as the source of reducing eEuivalents The purpose of these modifications is: a- it may itself activate or deactivate a drug, )- or ma$e a toxic compound more soluble, thus facilitating its excretion in the urine or feces reEuently, ho%ever, the ne% hydroxyl group %ill serve as a site for con>ugation %ith polar compound, such as glucuronic acid, %hich %ill significantly increase the compound(s solubility ?xcessive amounts of toxic chemicals such as pesticides can disrupt the *2 8<6 enyme system by causing hyper activity or %hat is called (induction( of this path%ay This %ill result in high levels of damaging free radicals being produced Substances that may cause hyperactivity of the *2 8<6 enymes: &affeine, Alcohol, Dioxin, Saturated fats, ;rganophosphorus pesticides, *aint fumes, Sulfonamides, ?xhaust fumes, Barbiturates Transforming a toxin to a more chemically reactive form ma$es it more easily metabolied by the phase II enymes If the phase II detoxification systems are not %or$ing adeEuately, these intermediates can cause substantial damage, including the initiation of carcinogenic processes ?ach enyme %or$s best in detoxifying certain types of chemicals, but %ith considerable overlap in activity among the enymes The activity of the various cytochrome *8<6 enymes varies significantly from one individual to another, based on genetics, the individual(s level of exposure to chemical toxins, and his or her nutritional status Since the activity of cytochrome *8<6 varies so much, so does an individual(s ris$ for various diseases This variability of cytochrome *8<6 enymes is seen in the variability of people(s ability to detoxify the carcinogens found in cigarette smo$e and helps to explain %hy some people can smo$e %ith only modest damage to their lungs, %hile others develop lung cancer after only a fe% decades of smo$ing LECTURE 4

Tuesday 4/10/2011

40


LECTURE 4

Tuesday 4/10/2011

A significant side2effect of phase I detoxification is the production of !ree radi"als as the toxins are transformed22for each molecule of toxin metabolied by phase I, one molecule of free radical is generated 0ithout adeEuate free radical defenses, every time the liver neutralies a toxin exposure, it is damaged by the free radicals produced The most important antioxidant for neutraliing the free radicals produced in phase I is glutathione In the process of neutraliing free radicals, ho%ever, glutathione 3.S+4 is oxidied to glutathione disul!ide 3.SS.4 .lutathione is reEuired for one of the $ey phase II detoxification processes 0hen high levels of toxin exposure produce so many free radicals from phase I detoxification that the glutathione is depleted, the phase II processes dependent upon glutathione stop, producing oxidative stress or liver damage The toxins transformed into activated intermediates by phase I are substantially more reactive than the phase I toxins %ere nless Euic$ly removed from the body by phase II detoxification mechanisms, they can cause %idespread problems, especially "ar"inogenesis Therefore, the rate at %hich phase I produces activated intermediates must be balanced by the rate at %hich phase II finishes their processing *eople %ith a very active phase I detoxification system coupled %ith slo% or inactive phase II enymes are termed pathologi"al detoxi!iers These people suffer unusually severe toxic reactions to environmental poisons An efficient liver detoxification system is vital to health and in order to support this process it is essential that many $ey nutrients are included in the diet /itamins and minerals O particularly the B vitamins O play a ma>or role, acting as cofactors for many enyme systems including those of liver detoxification Depletion of vitamin & may also impair the detoxification process vitamin & also prevents free radical formation /itamin ? and selenium are cofactors for glutathione peroxidase activity as %ell as being po%erful antioxidants ;ther nutrients %hich play vital roles in the *hase II path%ay include amino acids glycine, cysteine, glutamine, methionine, taurine, glutamic acid and aspartic acid .rapefruit >uice, %hich contains naringenin$ slo%s do%n *hase I enyme activity As %ith all enymes, the cytochrome *8<6s reEuire several nutrients to function, such as copper, magnesium, inc and vitamin &

41


LECTURE 4

Tuesday 4/10/2011

,hase $$ (etoxification This is called the co'u!atio pathway , %hereby the liver cells add another substance 3eg cysteine, glycine or a sulphur molecule4 to a toxic chemical or drug This ma$es the toxin or drug %ater2soluble, so it can then be excreted from the body via %atery fluids such as bile or urine Individual xenobiotics and metabolites usually follo% one or t%o distinct path%ays There are essentially six phase II detoxification path%ays: 1 .lutathione con>ugation ! Amino acid con>ugation 5 'ethylation 8 Sulfation < Acetylation 9 .lucuronidation 1. +!tathione conj!)ation A primary phase II detoxification route is "onugation %ith glutathione(γ -

glutamylcysteinylglycine), 3a tripeptide composed of three amino acids22 "ysteine$ glutai" a"id , and gly"ine4 .lutathione con>ugation produces %ater2 soluble er"aptates %hich are excreted via the $idneys The elimination of fat2soluble compounds, especially heavy metals li$e mercury and lead, is dependent upon adeEuate levels of glutathione, %hich in turn is dependent upon adeEuate levels of methioie and cysteie. 0hen increased levels of toxic compounds are present, more methionine is utilied for cysteine and glutathione synthesis 'ethionine and cysteine have a protective effect on glutathione and prevent depletion during toxic overload This, in turn, protects the liver from the damaging effects of toxic compounds and promotes their elimination If the availability of methionine is reduced, not only %ill the capability of the liver to detoxify be impaired, but there %ill also be less glutathione available to complex %ith foreign substances Studies have demonstrated that a deficiency of methionine can, in itself, cause liver cancer %ithout the presence of a carcinogen, and also that the deficiency of methionine can permit a heavy metal to cause toxic effects LECTURE 4

Tuesday 4/10/2011

42


LECTURE 4

Tuesday 4/10/2011

.lutathione is also an important antioxidant This combination of detoxification and free radical protection, results in glutathione being one of the most important anticarcinogens and antioxidants in our cells, %hich means that a deficiency is cause of serious liver dysfunction and damage ?xposure to high levels of toxins depletes glutathione faster than it can be produced or absorbed from the diet This results in increased susceptibility to toxin2induced diseases, such as cancer, especially if phase I detoxification system is highly active A deficiency can be induced either by diseases that increase the need for glutathione, deficiencies of the nutrients needed for synthesis, or diseases that inhibit its formation .lutathione is available through t%o routes: diet and synthesis Dietary glutathione 3found in fresh fruits and vegetables, coo$ed fish, and meat4 is absorbed %ell by the intestines and does not appear to be affected by the digestive processes Dietary glutathione in foods appears to be efficiently absorbed into the blood 2. Amino acid conj!)ation Several amino acids 3glyu"ine$ taurine$ glutaine$ arginine, and ornithine4 are used to combine %ith and neutralie toxins ;f these, glycine is the most commonly utilied in phase II amino acid detoxification *atients suffering from hepatitis, alcoholic liver disorders, carcinomas, chronic arthritis, hypothyroidism, toxemia of pregnancy, and excessive chemical exposure are commonly found to have a poorly functioning amino acid con>ugation system ?ven in normal adults, a %ide variation exists in the activity of the glycine con>ugation path%ay This is due not only to genetic variation, but also to the availability of glycine in the liver .lycine, and the other amino acids used for con>ugation, become deficient on a lo%2protein diet and %hen chronic exposure to toxins results in depletion 3. eth'ation 'ethylation involves con>ugating ethyl groups to toxins 'ost of the methyl groups used for detoxification comes from '7 adenosylethionine 3SA'4 SA' is synthesied from the amino acid methionine, a process %hich reEuires the nutrients choline, the active form of B1! 77ethyl "obalain, and the active form of folic acid 22/7 ethyltetrahydro!olate 'ethionine is a ma>or source of numerous sulfur2 containing compounds, including the amino acids cysteine and taurine

LECTURE 4

Tuesday 4/10/2011

43


4. !fation Sulfation is the con>ugation of toxins %ith sulfur2containing compounds The sulfation system is important for detoxifying several drugs, food additives, and, especially, toxins from intestinal bacteria and the environment In addition to environmental toxins, sulfation is also used to detoxify some normal body chemicals and is the main path%ay for the elimination of steroid and thyroid hormones Since sulfation is also the primary route for the elimination of neurotransmitters, dysfunction in this system may contribute to the development of some nervous system disorders 'any factors influence the activity of sulfate con>ugation or example, a diet lo% in methionine and cysteine has been sho%n to reduce sulfation 5. Acet'ation &on>ugation of toxins %ith a"etyl7Co- is the primary method by %hich the body eliminates sulfa drugs This system appears to be especially sensitive to genetic variation, %ith those having a poor acetylation system being far more susceptible to sulfa drugs and other antibiotics 0hile not much is $no%n about ho% to directly improve the activity of this system, it is $no%n that acetylation is dependent on thiamine, pantothenic acid, and vitamin & 6. +!c!"onidation .lucuronidation, the combining of glu"uroni" a"id %ith toxins, in *hase II can be reversed by Beta glucuronidase enymes produced by pathological bacteria and cause toxins to be reabsorbed increasing toxicity 'any of the commonly prescribed drugs are detoxified through this path%ay It also helps to detoxify aspirin, menthol, vanillin 3synthetic vanilla4, food additives such as benoates, and some hormones !foxidation Sulfoxidation is the process by %hich the sulfur2containing molecules in drugs and foods are metabolied It is also the process by %hich the body eliminates the sulfite food additives used to preserve many foods and drugs 7ormally, the enyme sul!ite oxidase (olybdenu dependentenye) metabolies sul!ites to safer sul!ates, %hich are then excreted in the urine Those %ith a poorly functioning sulfoxidation system, ho%ever, have an increased ratio of sulfite to sulfate in their urine Those %ith a poorly functioning sulfoxidation detoxification path%ay are more sensitive to sulfur2containing drugs and foods containing sulfur or sulfite additives Le#!ure 5 Le#!ure 5

Thursday 6/10/2011 Thursday 6/10/2011

44


SECRETION AND ABSORPTION IN THE SMALL INTESTINE The s&a(( in!es!ine is !he *$r!a( %$r a)s$r*!i$n $% "ir!ua((y a(( nu!rien!s in!$ )($$d. ,##$&*(ishin !his !rans*$r! re+uires )reain d$n (are su*ra&$(e#u(ar area!es in!$ s&a(( &$(e#u(es !ha! #an )e !rans*$r!ed a#r$ss !he e*i!he(iu&. y !he !i&e ines!a rea#hes !he s&a(( in!es!ine %$$ds!u%%s ha"e )een &e#hani#a((y )r$en d$n and redu#ed !$ a (i+uid )y &as!i#a!i$n and rindin in !he s!$&a#h. n#e i!hin !he s&a(( in!es!ine !hese &a#r$&$(e#u(ar area!es are e*$sed !$ *an#rea!i# eny&es and )i(e hi#h ena)(es dies!i$n !$ &$(e#u(es #a*a)(e $r a(&$s! #a*a)(e $% )ein a)s$r)ed. The %ina( s!aes $% dies!i$n $##ur $n !he sur%a#e $% !he s&a(( in!es!ina( e*i!he(iu&. The ne! e%%e#! $% *assae !hr$uh !he s&a(( in!es!ine is a)s$r*!i$n $% &$s! $% !he a!er and e(e#!r$(y!es s$diu& #h($ride *$!assiu& and essen!ia((y a(( die!ary $rani# &$(e#u(es in#(udin (u#$se a&in$ a#ids and %a!!y a#ids. Thr$uh !hese a#!i"i!ies !he s&a(( in!es!ine n$! $n(y *r$"ides nu!rien!s !$ !he )$dy )u! *(ays a #ri!i#a( r$(e in a!er and a#id)ase )a(an#e. Secretion in the Small Intestine

#arge Euantities of %ater are secreted into the lumen of the small intestine during the digestive process Almost all of this %ater is also reabsorbed in the small intestine )egardless of %hether it is being secreted or absorbed, %ater flo%s across the mucosa in response to osmotic gradients In the case of secretion, t%o distinct processes establish an osmotic gradient that pulls %ater into the lumen of the intestine: 1. $nc"eases in !mina osmotic *"ess!"e "es!tin) f"om inf!x and di)estion of foodst!ffs: 8he ch'me that foods into the intestine f"om the stomach t'*ica' is not h'*e"osmotic= b!t as its mac"omoec!a" com*onents a"e di)ested= osmoa"it' of that so!tion inc"eases d"amatica'. Starch, for example, is a huge molecule that contributes only a small amount to osmotic pressure, but as it is digested, thousands of molecules of maltose are generated, each of %hich is as osmotically active as the original starch molecule

Le#!ure 5

Thursday 6/10/2011 45


Thus, as digestion proceeds lumenal osmolarity increases dramatically and %ater is pulled into the lumen Then, as the osmotically active molecules 3maltose, glucose, amino acids4 are absorbed, osmolarity of the intestinal contents decreases and %ater can be absorbed 2. "'*t ces active' sec"ete eect"o'tes= eadin) to ate" sec"etion: 8he a*ica o" !mena memb"ane of c"'*t e*itheia ces contain an ion channe of immense medica si)nificance - a cyclic #P+depedet chloride chael ow also as the cystic fi)rosis trasmem)rae coductace re!ulator or CF(R- !tations in the )ene fo" this ion channe "es!t in the disease c'stic fib"osis. 8his channe is "es*onsibe fo" sec"etion of ate" b' the fooin) ste*s:

1 &hloride ions enter the crypt epithelial cell by cotransport %ith sodium and potassium sodium is pumped bac$ out via sodium pumps, and potassium is exported via a number of channels ! Activation of adenylyl cyclase by a number of so2called secretagogues leads to generation of cyclic A'* 5 ?levated intracellular concentrations of cA'* in crypt cells activate the &T), resulting in secretion of chloride ions into the lumen 8 Accumulation of negatively2charged chloride anions in the crypt creates an electric potential that attracts sodium, pulling it into the lumen, apparently across tight >unctions 2 the net result is secretion of 7a&l < Secretion of 7a&l into the crypt creates an osmotic gradient across the tight >unction and %ater is dra%n into the lumen

Le#!ure 5

Thursday 6/10/2011 $$A ##%A8$

Cystic fibrosis

46


,)n$r&a( a#!i"a!i$n $% !he #,'de*enden! #h($ride #hanne( CTR in #ry*! #e((s has resu(!ed in !he dea!hs $% &i((i$ns u*$n &i((i$ns $% *e$*(e. Se"era( !y*es $% )a#!eria *r$du#e !$ins !ha! s!r$n(y $%!en *er&anen!(y a#!i"a!e !he adeny(a!e #y#(ase in #ry*! en!er$#y!es. This (eads !$ e(e"a!ed (e"e(s $% #,' #ausin !he #h($ride #hanne(s !$ essen!ia((y )e#$&e s!u# in !he :$*en: *$si!i$n:. The resu(! is &assi"e se#re!i$n $% a!er !ha! is &ani%es! as se"ere diarrhea. Ch$(era !$in *r$du#ed )y #h$(era )a#!eria is !he )es! n$n ea&*(e $% !his *hen$&en$n )u! se"era( $!her )a#!eria *r$du#e !$ins !ha! a#! si&i(ar(y.

Abso"*tion in the ma $ntestine: +ene"a echanisms /irtually all nutrients from the diet are absorbed into blood across the mucosa of the small intestineTo remain viable, all cells are reEuired to maintain a lo% intracellular concentration of sodium In polaried epithelial cells li$e enterocytes, lo% intracellular sodium is maintained by a large number of 7a=M-= AT*ases 2 so2called sodium pumps 2 embedded in the basolateral membrane These pumps export 5 sodium ions from the cell in exchange for ! potassium ions, thus establishing a gradient of both charge and sodium concentration across the basolateral membrane

Aside from the electrochemical gradient of sodium, several other concepts are reEuired to understand absorption in the small intestine Also, dietary sources of protein, carbohydrate and fat must all undergo the final stages of chemical digestion >ust prior to absorption of, for example, amino acids, glucose and fatty acids • • • •

0ater and electrolytes &arbohydrates, after digestion to monosaccharides *roteins, after digestion to small peptides and amino acids 7eutral fat, after digestion to monoglyceride and free fatty acids

Le#!ure 5

Thursday 6/10/2011

1 Abso"*tion of
47


The s&a(( in!es!ine &us! a)s$r) &assi"e +uan!i!ies $% a!er. , n$r&a( *ers$n aes in r$uh(y 1 !$ 2 (i!ers $% die!ary %(uid e"ery day. n !$* $% !ha! an$!her 6 !$ 7 (i!ers $% %(uid is re#ei"ed )y !he s&a(( in!es!ine dai(y as se#re!i$ns %r$& sa(i"ary (ands s!$&a#h *an#reas (i"er and !he s&a(( in!es!ine i!se(%. y !he !i&e !he ines!a en!ers !he (are in!es!ine a**r$i&a!e(y 80; $% !his %(uid has )een a)s$r)ed.
•

•

•

Sodium is absorbed into the cell by several mechanisms, but chief among them is by co2transport %ith glucose and amino acids 2 this means that efficient sodium absorption is dependent on absorption of these organic solutes Absorbed sodium is rapidly exported from the cell via sodium pumps 2 %hen a lot of sodium is entering the cell, a lot of sodium is pumped out of the cell, %hich establishes a high osmolarity in the small intercellular spaces bet%een ad>acent enterocytes 0ater diffuses in response to the osmotic gradient established by sodium 2 in this case into the intercellular space It seems that the bul$ of the %ater absorption is transcellular, but some also diffuses through the tight >unctions 0ater, as %ell as sodium, then diffuses into capillary blood %ithin the villus

=a!er is !hus a)s$r)ed in!$ !he in!er#e((u(ar s*a#e )y di%%usi$n d$n an $s&$!i# radien!. >$e"er ($$in a! !he *r$#ess as a h$(e !rans*$r! $% a!er %r$& (u&en !$ )($$d is $%!en aains! an $s&$!i# radien!  !his is i&*$r!an! )e#ause i! &eans !ha! !he in!es!ine #an a)s$r) a!er in!$ )($$d e"en hen !he $s&$(ari!y in !he (u&en is hiher !han $s&$(ari!y $% )($$d.

2 Abso"*tion of onosaccha"ides $n$sa##harides are $n(y rare(y %$und in n$r&a( die!s. Ra!her !hey are deri"ed )y eny&a!i# dies!i$n $% &$re #$&*(e #ar)$hydra!es i!hin !he dies!i"e !u)e. 'ar!i#u(ar(y i&*$r!an! die!ary #ar)$hydra!es in#(ude s!ar#h and disa##harides su#h as (a#!$se and su#r$se. <$ne $% !hese &$(e#u(es #an )e a)s$r)ed %$r !he si&*(e reas$n !ha! !hey #ann$! #r$ss #e(( &e&)ranes unaided and un(ie !he si!ua!i$n %$r &$n$sa##harides !here are n$ !rans*$r!ers !$ #arry !he& a#r$ss.

>rush >order ydrolases Benerate Monosa""harides '$(ysa##harides and disa##harides &us! )e dies!ed !$ &$n$sa##harides *ri$r !$ a)s$r*!i$n and !he ey *(ayers in !hese *r$#esses are !he )rush )$rder hydr$(ases hi#h in#(ude &a(!ase (a#!ase and su#rase. Die!ary (a#!$se and su#r$se are :ready: %$r dies!i$n )y !heir res*e#!i"e )rush )$rder eny&es. S!ar#h as dis#ussed *re"i$us(y is %irs! dies!ed !$ &a(!$se )y a&y(ase in *an#rea!i# se#re!i$ns and sa(i"a. Le#!ure 5 Thursday 6/10/2011 Dietary lactose and sucrose, and maltose derived from digestion of starch, diffuse in the small intestinal lumen and come in contact %ith the surface of absorptive epithelial cells covering the villi %here they engage %ith brush border hydrolases: 48


maltase cleaves maltose into t%o molecules of glucose • lactase cleaves lactose into a glucose and a galactose • sucrase cleaves sucrose into a glucose and a fructose .lucose and galactose are ta$en into the enterocyte by cotransport %ith sodium using the same transporter ructose enters the cell from the intestinal l umen via facilitated diffusion through another transporter )sorptio of $lucose ad other #oosaccharides& (rasport across the testial 7pithelium Absorption of glucose entails transport from the intestinal lumen, across the epithelium and into blood The transporter that carries glucose and galactose into the enterocyte is the sodium2dependent hexose transporter, $no%n more formally as +B8-1. As the name indicates, this molecule transports both glucose and sodium ion into the cell and in fact, %ill not transport either alone The essence of transport by the sodium2dependent hexose transporter involves a series of conformational changes induced by binding and release of sodium and glucose, and can be summaried as follo%s: •

1 the transporter is initially oriented facing into the lumen 2 at this point it is capable of binding sodium, but not glucose ! sodium binds, inducing a conformational change that opens the glucose2binding poc$et 5 glucose binds and the transporter reorients in the membrane such that the poc$ets holding sodium and glucose are moved inside the cell 8 sodium dissociates into the cytoplasm, causing glucose binding to destabilie < glucose dissociates into the cytoplasm and the unloaded transporter reorients bac$ to its original, out%ard2facing position

ructose is not co2transported %ith sodium )ather it enters the enterocyte by another hexose transporter 3.#T<4 ;nce inside the enterocyte, glucose and sodium must be exported from the cell into blood Sodium is rapidly shuttled out in exchange for potassium by the battery of sodium pumps on the basolateral membrane, this process maintains the electrochemical gradient across the epithelium The massive transport of sodium out of the cell establishes the osmotic gradient responsible for absorption of %ater 

Dies!i$n and a)s$r*!i$n $% #ar)$hydra!es Le#!ure 5

Thursday 6/10/2011

CI!ICA C"##EA$I"!

49


Disaccharidase Deficiency ?n!es!ina( disa##haridase de%i#ien#ies are en#$un!ered re(a!i"e(y %re+uen!(y in hu&ans. De%i#ien#y #an )e *resen! in $ne eny&e $r se"era( eny&es %$r a "arie!y $% reas$ns ene!i# de%e#! *hysi$($i#a( de#(ine i!h ae $r !he resu(! $% :in@uries: !$ !he &u#$sa. % !he disa##haridases (a#!ase is !he &$s! #$&&$n eny&e i!h an a)s$(u!e $r re(a!i"e de%i#ien#y hi#h is e*erien#ed as &i( in!$(eran#e. The #$nse+uen#es $% an ina)i(i!y !$ hydr$(ye (a#!$se in !he u**er s&a(( in!es!ine are ina)i(i!y !$ a)s$r) (a#!$se and )a#!eria( %er&en!a!i$n $% ines!ed (a#!$se in !he ($er s&a(( in!es!ine. a#!eria( %er&en!a!i$n resu(!s in !he *r$du#!i$n $% as dis!ensi$n $% u! and %(a!u(en#e and $s&$!i#a((y a#!i"e s$(u!es !ha! dra a!er in!$ !he in!es!ina( (u&en diarrhea. The (a#!$se in y$ur! has a(ready )een *ar!ia((y hydr$(yed durin !he %er&en!a!i$n *r$#ess $% &ain y$ur!. Thus indi"idua(s i!h (a#!ase de%i#ien#y #an $%!en !$(era!e y$ur! )e!!er !han un%er&en!ed dairy *r$du#!s. The eny&e (a#!ase is #$&&er#ia((y a"ai(a)(e !$ *re!rea! &i( s$ !ha! !he (a#!$se is hydr$(yed.

3 Abso"*tion of Amino Acids and ,e*tides Dietary proteins are, %ith very fe% exceptions, not absorbed )ather, they must be digested into amino acids or di2 and tripeptides first, through the action of gastric and pancreatic proteases The brush border of the small intestine i s eEuipped %ith a family of peptidases #i$e lactase and maltase, these peptidases are integral membrane proteins rather than soluble enymes They function to further the hydrolysis of lumenal peptides, converting them to free amino acids and very small peptides These end products of digestion, formed on the surface of the enterocyte, are ready for absorption a8 )sorptio of mio cids The &e#hanis& )y hi#h a&in$ a#ids are a)s$r)ed is #$n#e*!ua((y iden!i#a( !$ !ha! $% &$n$sa##harides. The (u&ena( *(as&a &e&)rane $% !he a)s$r*!i"e #e(( )ears a! (eas! %$ur s$diu&de*enden! a&in$ a#id !rans*$r!ers  $ne ea#h %$r a#idi# )asi# neu!ra( and a&in$ a#ids. These !rans*$r!ers )ind a&in$ a#ids $n(y a%!er )indin s$diu&. The %u((y ($aded !rans*$r!er !hen under$es a #$n%$r&a!i$na( #hane !ha! du&*s s$diu& and !he a&in$ a#id in!$ !he #y!$*(as& %$(($ed )y i!s re$rien!a!i$n )a# !$ !he $riina( %$r&. Thus a)s$r*!i$n $% a&in$ a#ids is a(s$ a)s$(u!e(y de*enden! $n !he e(e#!r$#he&i#a( radien! $% s$diu& a#r$ss !he e*i!he(iu&. ur!her a)s$r*!i$n $% a&in$ a#ids (ie !ha! $% &$n$sa##harides #$n!ri)u!es !$ enera!in !he $s&$!i# radien! !ha! dri"es a!er a)s$r*!i$n. The )as$(a!era( &e&)rane $% !he en!er$#y!e #$n!ains addi!i$na( !rans*$r!ers hi#h e*$r! a&in$ a#ids %r$& !he #e(( in!$ )($$d. These are n$! de*enden! $n s$diu& radien!s.

Le#!ure 5 CI!ICA C"##EA$I"! !eutral Amino Aciduria %&artnup Disease'

Thursday 6/10/2011

50


Trans*$r! %un#!i$ns (ie eny&a!i# %un#!i$ns are su)@e#! !$ &$di%i#a!i$n )y &u!a!i$ns. ,n ea&*(e $% a ene!i# (esi$n in e*i!he(ia( a&in$ a#id !rans*$r! is >ar!nu* disease na&ed a%!er !he %a&i(y in hi#h !he disease en!i!y resu(!in %r$& !he de%e#! as %irs! re#$nied. The disease is #hara#!eried )y !he ina)i(i!y $% rena( and in!es!ina( e*i!he(ia( #e((s !$ a)s$r) neu!ra( a&in$ a#ids %r$& !he (u&en. ?n !he idney in hi#h *(as&a a&in$ a#ids rea#h !he (u&en $% !he *r$i&a( !u)u(e !hr$uh !he u(!ra%i(!ra!e !he ina)i(i!y !$ rea)s$r) a&in$ a#ids &ani%es!s i!se(% as e#re!i$n $% a&in$ a#ids in !he urine a&in$ a#iduria. The in!es!ina( de%e#! resu(!s in &a(a)s$r*!i$n $% %ree a&in$ a#ids %r$& !he die!. There%$re !he #(ini#a( sy&*!$&s $% *a!ien!s i!h !his disease are &ain(y !h$se due !$ essen!ia( a&in$ a#id and ni#$!ina&ide de%i#ien#ies. The *e((ara(ie %ea!ures are e*(ained )y a de%i#ien#y $% !ry*!$*han hi#h ser"es as *re#urs$r %$r ni#$!ina&ide. ?n"es!ia!i$ns $% *a!ien!s i!h >ar!nu* disease re"ea(ed !he eis!en#e $% in!es!ina( !rans*$r! sys!e&s %$r di $r !ri*e*!ides hi#h are di%%eren! %r$& !he $nes %$r %ree a&in$ a#ids. The ene!i# (esi$n d$es n$! a%%e#! !rans*$r! $% *e*!ides hi#h re&ains as a *a!hay %$r a)s$r*!i$n $% *r$!ein dies!i$n *r$du#!s )8 )sorptio of Peptides There is "ir!ua((y n$ a)s$r*!i$n $% *e*!ides ($ner !han %$ur a&in$ a#ids. >$e"er !here is a)undan! a)s$r*!i$n $% di and !ri*e*!ides in !he s&a(( in!es!ine. These s&a(( *e*!ides are a)s$r)ed in!$ !he s&a(( in!es!ina( e*i!he(ia( #e(( )y #$!rans*$r! i!h > A i$ns "ia a !rans*$r!er #a((ed 'e*T1. n#e inside !he en!er$#y!e !he "as! )u( $% a)s$r)ed di and !ri*e*!ides are dies!ed in!$ a&in$ a#ids )y #y!$*(as&i# *e*!idases and e*$r!ed %r$& !he #e(( in!$ )($$d. n(y a "ery s&a(( nu&)er $% !hese s&a(( *e*!ides en!er )($$d in!a#!.

c8 )sorptio of tact Proteis ,)s$r*!i$n $% in!a#! *r$!eins $##urs $n(y in a %e #ir#u&s!an#es. <$r&a(: en!er$#y!es d$ n$! ha"e !rans*$r!ers !$ #arry *r$!eins a#r$ss !he *(as&a &e&)rane and !hey #er!ain(y #ann$! *er&ea!e !ih! @un#!i$ns. ne i&*$r!an! e#e*!i$n is !ha! %$r a "ery %e days a%!er )ir!h ne$na!es ha"e !he a)i(i!y !$ a)s$r) in!a#! *r$!eins. This a)i(i!y hi#h is ra*id(y ($s! is $% i&&ense i&*$r!an#e )e#ause i! a(($s !he ne)$rn ani&a( !$ a#+uire *assi"e i&&uni!y )y a)s$r)in i&&un$($)u(ins in #$($s!ra( &i(. The s&a(( in!es!ine ra*id(y ($ses !he #a*a#i!y !$ a)s$r) in!a#! *r$!eins. 4 Abso"*tion of i*ids The )u( $% die!ary (i*id is neu!ra( %a! $r !ri(y#eride #$&*$sed $% a (y#er$( )a#)$ne i!h ea#h #ar)$n (ined !$ a %a!!y a#id. ,ddi!i$na((y &$s! %$$ds!u%%s #$n!ain *h$s*h$(i*ids s!er$(s (ie #h$(es!er$( and &any &in$r (i*ids in#(udin %a!s$(u)(e "i!a&ins. ?n $rder %$r !he !ri(y#eride !$ )e a)s$r)ed !$ *r$#esses &us! $##ur• #arge aggregates of dietary triglyceride, %hich are virtually insoluble in an aEueous environment, must be bro$en do%n physically and held in suspension 2 a process called emulsification • Triglyceride molecules must be enymatically digested to yield monoglyceride and fatty acids, both of %hich can efficiently diffuse into the enterocyte The ey *(ayers in !hese !$ !rans%$r&a!i$ns are bile salts and pancreatic lipase )$!h $% hi#h are &ied i!h #hy&e and a#! in !he (u&en $% !he s&a(( in!es!ine. Le#!ure 5

Thursday 6/10/2011

51


Dies!i$n and a)s$r*!i$n $% (i*ids

han)es in *h'sica state d!"in) t"iac')'ce"o di)estion. Abb"eviations: 8+= t"iac')'ce"oC (+= diac')'ce"oC += monoac')'ce"oC A= fatt' a cid

$$A ##%A8$ A- -i*o*"oteinemia A2b2lipoproteinemia is an autosomal recessive disorder characteried by the absence of all lipoproteins containing apo2 2lipoprotein, that is, chylomicrons, very lo% density lipoproteins 3/#D#s4, and lo% density lipoproteins 3#D#s4 Serum cholesterol is extremely lo% This defect is associated %ith severe malabsorption of triacylglycerol and lipid2soluble vitamins 3especially tocopherol and vitamin ?4 and accumulation of apo B in enterocytes and hepatocytes The defect does not appear to involve the gene for apo B, but rather one of several proteins involved in processing of apo B in liver and intestinal mucosa, or in assembly and secretion of triacylglycerol2rich lipoproteins, that is, chylomicrons and /#D#s from these tissues, respectively

52


Le#!ure 5

Thursday 6/10/2011

5 Abso"*tion of ine"as and etas The "as! )u( $% &inera( a)s$r*!i$n $##urs in !he s&a(( in!es!ine. The )es!s!udied &e#hanis&s $% a)s$r*!i$n are #(ear(y %$r #a(#iu& and ir$n de%i#ien#ies $% hi#h are sini%i#an! hea(!h *r$)(e&s !hr$uh$u! !he $r(d.

a8 Calcium The +uan!i!y $% #a(#iu& a)s$r)ed in !he in!es!ine is #$n!r$((ed )y h$ &u#h #a(#iu& has )een in !he die! durin re#en! *eri$ds $% !i&e. Ca(#iu& is a)s$r)ed )y !$ dis!in#! &e#hanis&s1. !cti"e# transcellular absorption $##urs $n(y in !he du$denu& hen #a(#iu& in!ae has )een ($. This *r$#ess in"$("es i&*$r! $% #a(#iu& in!$ !he en!er$#y!e !rans*$r! a#r$ss !he #e(( and e*$r! in!$ e!ra#e((u(ar %(uid and )($$d. The ra!e (i&i!in s!e* in !rans#e((u(ar #a(#iu& a)s$r*!i$n is !rans*$r! a#r$ss !he e*i!he(ia( #e(( hi#h is rea!(y enhan#ed )y !he #arrier *r$!ein #a()indin !he syn!hesis $% hi#h is !$!a((y de*enden! $n "i!a&in D. 2. Passi"e# paracellular absorption $##urs in !he @e@unu& and i(eu& and !$ a &u#h (esser e!en! in !he #$($n hen die!ary #a(#iu& (e"e(s ha"e )een &$dera!e $r hih. ?n !his #ase i$nied #a(#iu& di%%uses !hr$uh !ih! @un#!i$ns in!$ !he )as$(a!era( s*a#es ar$und en!er$#y!es and hen#e in!$ )($$d. Su#h !rans*$r! de*ends $n ha"in hiher #$n#en!ra!i$ns $% %ree #a(#iu& in !he in!es!ina( (u&en !han in )($$d.

)8 Phosphorus 'h$s*h$rus is *red$&inan!(y a)s$r)ed as in$rani# *h$s*ha!e in !he u**er s&a(( in!es!ine. 'h$s*ha!e is !rans*$r!ed in!$ !he e*i!he(ia( #e((s )y #$!rans*$r! i!h s$diu& and e*ressi$n $% !his $r !hese !rans*$r!ers is enhan#ed )y "i!a&in D.

c8 ro ?r$n h$&e$s!asis is reu(a!ed a! !he (e"e( $% in!es!ina( a)s$r*!i$n and i! is i&*$r!an! !ha! ade+ua!e )u! n$! e#essi"e +uan!i!ies $% ir$n )e a)s$r)ed %r$& !he die!. ?nade+ua!e a)s$r*!i$n #an (ead !$ ir$nde%i#ien#y dis$rders su#h as ane&ia. n !he $!her hand e#essi"e ir$n is !$i# )e#ause &a&&a(s d$ n$! ha"e a *hysi$($i# *a!hay %$r i!s e(i&ina!i$n.

53


Le#!ure 5

Thursday 6/10/2011

?r$n is a)s$r)ed )y "i((us en!er$#y!es in !he *r$i&a( du$denu&. E%%i#ien! a)s$r*!i$n re+uires an acidic en"ir$n&en!. erri# ir$n eAAA in !he du$dena( (u&en is redu#ed !$ i!s %err$us %$r& !hr$uh !he a#!i$n $% a )rush )$rder %erriredu#!ase. ?r$n is !hen #$ !rans*$r!ed i!h a *r$!$n in!$ !he en!er$#y!e "ia !he di"a(en! &e!a( !rans*$r!er DT1. This !rans*$r!er is n$! s*e#i%i# %$r ir$n and a(s$ !rans*$r!s &any di"a(en! &e!a( i$ns. n#e inside !he en!er$#y!e ir$n %$(($s $ne $% !$ &a@$r *a!hays•

%ron abundan"e states: iron %ithin the enterocyte is trapped by incorporation into ferritin and hence, not transported into blood 0hen the enterocyte dies and is shed, this iron is lost

•

%ron liiting states: iron is exported out of the enterocyte via a transporter 3ferroportin4 located in the basolateral membrane It then binds to the iron2 carrier transferrin for transport throughout the body

d8 Copper There a**ear !$ )e !$ *r$#esses res*$nsi)(e %$r #$**er a)s$r*!i$ni a ra*id ($ #a*a#i!y sys!e& and ii a s($er hih #a*a#i!y sys!e& hi#h &ay )e si&i(ar !$ !he !$ *r$#esses seen i!h #a(#iu& a)s$r*!i$n. any $% !he &$(e#u(ar de!ai(s $% #$**er a)s$r*!i$n re&ain !$ )e e(u#ida!ed. ?na#!i"a!in &u!a!i$ns in !he ene en#$din an in!ra#e((u(ar #$**er ,T'ase ha"e )een sh$n res*$nsi)(e %$r !he %ai(ure $% in!es!ina( #$**er a)s$r*!i$n in enes disease. , nu&)er $% die!ary %a#!$rs ha"e )een sh$n !$ in%(uen#e #$**er a)s$r*!i$n. $r ea&*(e e#essi"e die!ary in!ae $% ei!her in# $r &$(y)denu& #an indu#e se#$ndary #$**er de%i#ien#y s!a!es.

e8 9ic Bin# h$&e$s!asis is (are(y reu(a!ed )y i!s u*!ae and ($ss !hr$uh !he s&a(( in!es!ine. ,(!h$uh a nu&)er $% in# !rans*$r!ers and )indin *r$!eins ha"e )een iden!i%ied in "i((us e*i!he(ia( #e((s a de!ai(ed *i#!ure $% !he &$(e#u(es in"$("ed in in# a)s$r*!i$n is n$! ye! in hand. , nu&)er $% nu!ri!i$na( %a#!$rs ha"e )een iden!i%ied !ha! &$du(a!e in# a)s$r*!i$n. Cer!ain ani&a( *r$!eins in !he die! enhan#e in# a)s$r*!i$n. 'hy!a!es %r$& die!ary *(an! &a!eria( in#(udin #erea( rains #$rn ri#e #he(a!e in# and inhi)i! i!s a)s$r*!i$n. Su)sis!en#e $n *hy!a!eri#h die!s is !h$uh! res*$nsi)(e %$r a #$nsidera)(e %ra#!i$n $% hu&an in# de%i#ien#ies.

54


Le#!ure 6

Sunday 9/10/2011

ec"etion and Abso"*tion in the a")e $ntestine The large intestine is the last attraction in digestive tube and the location of the terminal phases of digestion It functions in three processes: • #ecove"' of ate" and eect"o'tes f"om in)esta: By the time ingesta reaches the terminal ileum, roughly F6 of its %ater has been absorbed, but considerable %ater and electrolytes li$e sodium and chloride remain and must be recovered by absorption in the large gut • o"mation and sto"a)e of feces: • ic"obia fe"mentation: The large intestine of all species teems %ith microbial life Those microbes produce enymes capable of digesting many of molecules that to vertebrates are indigestible, cellulose being a premier example The extent and benefit of fermentation also varies greatly among species Abso"*tion= ec"etion and o"mation of eces in the a")e $ntestine 1 Absorption: %ater, sodium ions and chloride ions ! Secretion: bicarbonate ions and mucus 0ater, as al%ays, is absorbed in response to an osmotic gradient The mechanism responsible for generating this osmotic pressure is essentially identical to %hat %as seen in the small intestine 2 sodium ions are transported from the lumen across the epithelium by virtue of the epithelial cells having very active sodium pumps on their basolateral membranes and a means of absorbing sodium through their lumenal membranes The colonic epithelium is actually more efficient at absorbing %ater than the small intestine and sodium absorption in the colon is enhanced by the hormone aldosterone &hloride is absorbed by exchange %ith bicarbonate The resulting secretion of bicarbonate ions into the lumen aids in neutraliation of the acids generated by microbial fermentation in the large gut

55


Le#!ure 6

Sunday 9/10/2011

$de( %$r e(e#!r$eni#
This 7a flux is electrogenic that is, it is associated %ith an electrical current, and it can be inhibited by the diuretic drug amiloride at micromolar concentrations

ic"obia e"mentation ermentation is the enymatic decomposition and utililiation of foodstuffs, particularly carbohydrates, by microbes The large intestine does not produce its o%n digestive enymes, but contains huge numbers of bacteria %hich have the enymes to digest and utilie many substrates In all animals, t%o processes are attributed to the microbial flora of the large intestine: 1 Digestion of carbohydrates not digested in the small intestine ! Synthesis of vitamin - and certain B vitamins &ellulose is common constituent in the diet of many animals, including man, but no mammalian cell is $no%n to produce a cellulase Several species of bacteria in the large bo%el synthesie cellulases and digest cellulose Importantly, the ma>or end products of microbial digestion of cellulose and other carbohydrates are volatile fatty acids, lactic acid, methane, hydrogen and carbon dioxide ermentation is thus the ma>or source of intestinal gas /olatile fatty acids 3acetic, proprionic and butyric acids4 generated from fermentation can be absorbed by diffusion in the colon Synthesis of vitamin - by colonic bacteria provides a valuable supplement to dietary sources and ma$es clinical vitamin - deficiency rare Similarly, formation of B vitamins by the microbial flora in the large intestine is useful to many animals They are not absorbed in the large intestine, but are present in feces

56


Le#!ure 6

Sunday 9/10/2011

$ntestina +as ,"od!ction A considerable amount of gas is present in the gastrointestinal contents of all animals ive gases constitute greater than FF of the gases passed: 7!, ;!, &;!, +! and methane 7one of these gases has an odor, and the characteristic odor of feces i s due to very small Euantities of a fe% other gases, including hydrogen sulfide There are three principal sources of the five ma>or intestinal gases: 1 Air s%allo%ing is the ma>or source of gas in the stomach ! Intraluminal generation of gases results from t%o ma>or processes First , in the proximal intestine, the interaction of hydrogen and bicarbonate ions 3principally from gastric and pancreatic secretions4 leads to generation of &;! The amount of gas generated by this path%ay is not great, because the lumenal contents do not contain carbonic anhydrase and the dissociation of +!&;5 is thus Euite slo% Additionally, most of the &;! produced in this %ay is absorbed into blood (he secod and much more productive source of gas is fermentation by colonic bacteria 'icrobes appear to be the sole source of all of the hydrogen and methane produced in the intestine A variety of fruits and vegetables contain polysaccharides that are not digested in the small intestine and lead to voluminous gas production by microbes Indeed, the primary medical treatment for excessive gas production is dietary manipulation to eliminate foodstuffs that the individual cannot digest and absorb

8he +ast"ointestina ;a""ie" The gastrointestinal mucosa forms a barrier bet%een the body and a lumenal environment %hich not only contains nutrients, but is loaded %ith potentially hostile microorganisms and toxins The challenge is to allo% efficient transport of nutrients across the epithelium %hile rigorously excluding passage of harmful molecules and organisms into the animal The exclusionary properties of the gastric and intestinal mucosa are referred to as the "gastrointestinal barrier8. The gastrointestinal barrier is often discussed as having t%o components: 1 The intrinsic barrier is composed of the epithelial cells lining the digestive tube and the tight >unctions that tie them together ! The extrinsic barrier consists of secretions and other influences that are not physically part of the epithelium, but %hich affect the epithelial cells and maintain their barrier function a 'ucus and Bicarbonate

57


Le#!ure 6

Sunday 9/10/2011

The entire gastrointestinal epithelium is coated %ith mucus, %hich serves an important role in mitigating shear stresses on the epithelium and contributes to barrier function in several %ays The abundant carbohydrates on mucin molecules bind to bacteria, %hich aids in preventing epithelial coloniation and, by causing aggregation, accelerates clearance Diffusion of hydrophilic molecules is considerably lo%er in mucus than in aEueous solution, %hich is thought to retard diffusion of a variety of damaging chemicals, including gastr ic acid, to the epithelial surface b +ormones and &yto$ines 7ormal proliferation of gastric and intestinal epithelial cells, as %ell as proliferation in response to such in>ury as ulceration, is $no%n to be affected by a large number of endocrine and paracrine factors Several of the enteric hormones are $no%n to enhance rates of proliferation Different forms of in>ury to the epithelium can lead to either enhanced or suppressed rates of cell proliferation *rostaglandins, particularly prostaglandin ?! and prostacyclin, have long been $no%n to have "cytoprotective" effects on the gastrointestinal epithelium A common clinical correlate in many mammals is that use of aspirin and other non2steroidal antiinflammatory drugs 37SAIDs4 %hich inhibit prostaglandin synthesis is commonly associated %ith gastric erosions and ulcers c Antibiotic *eptides and Antibodies

58


Le#!ure 6

Sunday 9/10/2011

:i!estive :isorders 1- Stomach ad testie *eptic ulcers Pepti" ul"er is a general term that refers to ulcers occurring in the lo%er esophagus, the stomach, or the duodenum 3upper part of the small intestine4

Sunday 9/10/2011

59


affeine &affeine seems to stimulate acid secretion in the stomach, %hich can aggravate the pain of an existing ulcer +o%ever, the stimulation of stomach acid cannot be attributed solely to caffeine • Acoho Although no proven lin$ has been found bet%een alcohol consumption and peptic ulcers, ulcers are more common in people %ho have cirrhosis of the liver, a disease often lin$ed to heavy alcohol consumption • t"ess 'ucos +&;5 content creates a "micro2environment" around surface cells to prevent acid damage, but its secretion is inhibited by adrenergic input 3prominent in stressP4 • Acid and *e*sin It is believed that the stomach(s inability to defend itself against the po%erful digestive fluids, hydrochloric acid and pepsin, contributes to ulcer formation • nonste"oida anti-infammato"' d"!)s A$(s These drugs 3such as aspirin, ibuprofen, and naproxen sodium4 ma$e the stomach vulnerable to the harmful effects of acid and pepsin •

2- ;ile ad the ;iliary System a- $allstoes or types of gallstones, %hich form due to distinctly different pathogenetic mechanisms 1 &holesterol Stones About F6 of gallstones are of this type These stones can be almost pure cholesterol or mixtures of cholesterol and substances such as mucin The $ey event leading to formation and progression of cholesterol stones is precipitation of cholesterol in bile There are clearly important genetic determinants for cholesterol stone formation There is also an important gender bias in development of stones 2 the prevalence in adult females is t%o to three times that seen in males and use of contraceptive steroids is a ris$ factor for development of gallstones ! *igment Stones )oughly 16 of human gallstones are pigment stones composed of large Euantities of bile pigments, along %ith lesser amounts of cholesterol and calcium salts The most important ris$ factor for development of these stones is chronic hemolysis from almost any cause 2 bilirubin is a ma>or constituent of these stones Additionally, some forms of pigment stones are associated %ith bacterial infections Apparently, some bacteria release decon>ugate bilirubin, leading to precipitation as calcium salts Le#!ure 6

Sunday 9/10/2011

60


)- %audice Qaundice, is yello%ing of the s$in, sclera 3the %hite of the eyes4 and mucous membranes caused by increased levels of bilirubin in the human body sually the concentration of bilirubin in the blood must exceed !2 5mgMd# for the coloration to be easily visible Qaundice comes from the rench %ord >aune, meaning yello%

Causes of 'audice 0hen red blood cells die, the heme in their hemoglobin is converted to bilirubin in the spleen The bilirubin is processed by the liver, enters bile and is eventually excreted through faeces &onseEuently, there are three different classes of causes for >aundice ,"e-he*atic or hemolytic causes, %here too many red blood cells are bro$en do%n, he*atic causes %here the processing of bilirubin in the liver does not function correctly, and *ost-he*atic or extrahepatic causes, %here the removal of bile is disturbed 1. ,"e-he*atic *re2hepatic 3or hemolytic4 >aundice is caused by anything %hich causes an increased rate of hemolysis 3brea$do%n of red blood cells4 'alaria can cause >aundice &ertain genetic diseases, such as glucose 92 phosphate dehydrogenase deficiency can lead to increase red cell lysis and therefore hemolytic >aundice Defects in bilirubin metabolism also present as >aundice 2. ?e*atic +epatic causes include acute hepatitis, hepatotoxicity and alcoholic liver disease Qaundice commonly seen in the ne%born baby is another example of hepatic >aundice

Le#!ure 6

Sunday 9/10/2011 61


7eonatal >aundice 7eonatal >aundice is usually harmless: this condition is often seen in infants around the second day after birth, lasting till day  in normal births, or to around day 18 in premature births Serum bilirubin normally drops to a lo% level %ithout any intervention reEuired: the >aundice is presumably a conseEuence of metabolic and physiological ad>ustments after birth Infants %ith neonatal >aundice are typically treated by exposing them to high levels of colored light to brea$ do%n the bilirubin •

Le#!ure 6

Sunday 9/10/2011

This %or$s due to a photo oxidation process occurring on the bilirubin in the subcutaneous tissues of the neonate #ight energy creates isomeriation of the bilirubin and conseEuently transformation into compounds that the ne% born can excrete via urine and stools 3. ,ost-he*atic *ost2hepatic 3or obstructive4 >aundice, also called cholestasis, is caused by an interruption to the drainage of bile in the biliary system The most common causes are gallstones in the common bile duct and pancreatic cancer in the head of the pancreas The van den Bergh test: 0hen a mixture of sulphanic acid, h ydrochloric acid and sodium nitrite 3diao reagent4 is added to serum containing an excess of biliriubin glucuronide a reddish2violet color results, the maximum color intensity being reached %ithin 56 seconds 3direct reaction4 3for hepatic and post hepatic >aundice4 0hen the same above reagents are mixed %ith serum containing an excess of billirubin itself or bilirubi2protien complex no color develops until alcohol is added, then the reddish2violet color appears3indirect reaction4 3for pre hepatic >aundice4 7ote: the addition of alcohol solvent provides the means of solution for the %ater insoluble bilirubin %hich is thus enabled to react %ith the diao reagent

c- Cirrhosis &irrhosis is characteried anatomically by %idespread nodules in the liver combined %ith fibrosis The fibrosis and nodule formation causes distortion of the normal liver architecture %hich interferes %ith blood flo% through the liver &irrhosis can also lead to an inability of the liver to perform its biochemical functions &auses of &irrhosis • Alcoholic liver disease • &hronic viral hepatitis B, & and D • &hronic autoimmune hepatitis • Inherited metabolic diseases • &hronic bile duct diseases • &hronic congestive heart failure infections • *arasitic infections • liver inflammation that can be caused by fatty liver • long term exposure to toxins or drugs

62


Le#!ure 6

Sunday 9/10/2011

3- testie Diarrhea is an increase in the volume of stool or freEuency of defecation It is one of the most common clinical signs of gastrointestinal disease, but also can reflect primary disorders outside of the digestive system There are numerous causes of diarrhea, but in almost all cases, this disorder is a manifestation of one of the four basic mechanisms described belo% 1 ;smotic Diarrhea Absorption of %ater in the intestines is dependent on adeEuate absorption of solutes If excessive amounts of solutes are retained in the intestinal lumen, %ater %ill not be absorbed and diarrhea %ill result ;smotic diarrhea typically results from one of t%o situations: • $n)estion of a *oo"' abso"bed s!bst"ate: The offending molecule is usually a carbohydrate or divalent ion &ommon examples include mannitol or sorbitol, epson salt 3'gS;84 and some antacids 3'g;+!4 • 'alabsorption: Inability to absorb certain carbohydrates is the most common deficit in this category of diarrhea, but it can result virtually any type of malabsorption A common example is lactose intolerance resulting from a deficiency in the brush border enyme lactase In such cases, a moderate Euantity of lactose is consumed 3usually as mil$4, but the intestinal epithelium is deficient in lactase, and lactose cannot be effectively hydrolyed into glucose and galactose for absorption The osmotically2active lactose is retained in the intestinal lumen, %here it "holds" %ater • A distinguishing feature of osmotic diarrhea is that it stops after the patient is fasted or stops consuming the poorly absorbed solute ! Secretory Diarrhea #arge volumes of %ater are normally secreted into the small intestinal lumen, but a large ma>ority of this %ater is efficiently absorbed before reaching the large intestine Diarrhea occurs %hen secretion of %ater into the intestinal lumen exceeds absorption 'any millions of people have died of the secretory diarrhea associated %ith cholera The responsible organism, /ibrio cholerae, produces cholera toxin, %hich strongly activates adenylyl cyclase, causing a prolonged increase in intracellular concentration of cyclic A'* %ithin crypt enterocytes This change results in prolonged opening of the chloride channels that are instrumental in secretion of %ater from the crypts, allo%ing uncontrolled secretion of %ater ?xposure to toxins from several other types of bacteria 3eg ? coli heat2 labile toxin4 induce the same series of steps and massive secretory 63


The Biochemistry of Digestion, Absorption and Detoxification by Prof. Dr. Hedef D. El-Yassin (1)

Recommend Documents