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

7/24/2019 The Biochemistry of Digestion, Absorption and Detoxification by Prof. Dr. Hedef D. El-Yassin (1)

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Biochemistry of Digestion, Absorption andDetoxification

27/9-9/10/2011

1. Lecture 1: Introduction to the Biochemistry of Digestion, absorption and detoxification.2. Lecture 2: Digestion and Digestive secretion from mouth and stomach3. Lecture 3: Digestive secretion from pancreas and liver4. Lecture 4: Detoxification in the liver5. Lecture 5: Secretion and absorption in the small intestine6. 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 food1 The absorption of basic nutrients! The detoxification mechanism

#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 Biochemistry" by *&&hampe, )A+arvey andD)errier (additional reading)

4. "+arper(s Biochemistry" by )-'urray, D-.ranner, *A 'ayes and /0)od%ell(additional reading)

Prof. Dr.H.D.El-Yassin

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LECTURE 1 Tuesday 27/9/2011

Introduction to the Biochemistry of Digestion,

Absorption and Detoxification$nt"od!ctionDigestion is the chemical brea$do%n of large food molecules into smallermolecules that can be used by cells The brea$do%n occurs %hen certainspecific enymes are mixed %ith the food

%n&'mes invoved in (i)estion

*o'saccha"ides matose )!cose

*"oteins *e*tides amino acids

fats fatt' acids and )'ce"o


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http://faculty.clintoncc.suny.edu/faculty/michael.gregory/files/Bio%20101/Bio%20101%20Lectures/Biochemistry/biochemi.htm#Polysaccharideshttp://faculty.clintoncc.suny.edu/faculty/michael.gregory/files/Bio%20101/Bio%20101%20Lectures/Biochemistry/biochemi.htm#Disaccharideshttp://faculty.clintoncc.suny.edu/faculty/michael.gregory/files/Bio%20101/Bio%20101%20Lectures/Biochemistry/biochemi.htm#Monosaccharideshttp://faculty.clintoncc.suny.edu/faculty/michael.gregory/files/Bio%20101/Bio%20101%20Lectures/Biochemistry/biochemi.htm#Proteinshttp://faculty.clintoncc.suny.edu/faculty/michael.gregory/files/Bio%20101/Bio%20101%20Lectures/Biochemistry/biochemi.htm#Polypeptideshttp://faculty.clintoncc.suny.edu/faculty/michael.gregory/files/Bio%20101/Bio%20101%20Lectures/Biochemistry/biochemi.htm#Amino%20Acidshttp://faculty.clintoncc.suny.edu/faculty/michael.gregory/files/Bio%20101/Bio%20101%20Lectures/Biochemistry/biochemi.htm#Fats%20and%20Oils%20(Triglycerideshttp://faculty.clintoncc.suny.edu/faculty/michael.gregory/files/Bio%20101/Bio%20101%20Lectures/Biochemistry/biochemi.htm#Disaccharideshttp://faculty.clintoncc.suny.edu/faculty/michael.gregory/files/Bio%20101/Bio%20101%20Lectures/Biochemistry/biochemi.htm#Monosaccharideshttp://faculty.clintoncc.suny.edu/faculty/michael.gregory/files/Bio%20101/Bio%20101%20Lectures/Biochemistry/biochemi.htm#Proteinshttp://faculty.clintoncc.suny.edu/faculty/michael.gregory/files/Bio%20101/Bio%20101%20Lectures/Biochemistry/biochemi.htm#Polypeptideshttp://faculty.clintoncc.suny.edu/faculty/michael.gregory/files/Bio%20101/Bio%20101%20Lectures/Biochemistry/biochemi.htm#Amino%20Acidshttp://faculty.clintoncc.suny.edu/faculty/michael.gregory/files/Bio%20101/Bio%20101%20Lectures/Biochemistry/biochemi.htm#Fats%20and%20Oils%20(Triglycerideshttp://faculty.clintoncc.suny.edu/faculty/michael.gregory/files/Bio%20101/Bio%20101%20Lectures/Biochemistry/biochemi.htm#Polysaccharides


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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 hugemacromolecules that cannot be absorbed into blood %ithout first beingreduced to much simpler and smaller forms The most important enymaticreaction in digestion of foodstuffs is hydrolysis 2 the brea$ing of a chemicalbond by the addition of a %ater molecule

Proteins

*roteins are polymers of amino acids lin$ed together by peptide bonds &hainlength varies tremendously and many dietary proteins have been modifiedafter translation by addition of carbohydrate 3glycoproteins4 or lipid3lipoprotein4 moieties /ery short proteins, typically 5 to 16 amino acids inlength, are called peptides

Lipids

atty acids are present in only small amounts in animal and plant tissues, butare the building bloc$s of many important complex lipids True fatty acidspossess a long hydrocarbon chain terminating 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 acidsare the length of the chain 3usually 19 or 1 carbons4 and the positions ofunsaturated or double bonds

The most abundant storage form of fat in animals and plants, and hence themost important dietary lipid, is triglyceride A molecule of triglyceride iscomposed of a molecule of glycerol in %hich each of the three carbons islin$ed through an ester bond to a fatty acid Triglycerides cannot be efficientlyabsorbed, and are enymatically digested by pancreatic lipase into a !2monoglyceride and t%o free fatty acids, all of %hich can be absorbed ;therlipases hydrolyse a triglyceride into glycerol and three fatty acids



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Carbohydrates

1 'onosaccharidesor simple sugars are either hexoses 392carbon4 li$eglucose, galactose and fructose, or pentoses 3or plant storage form of glucose It occurs in t%o forms:alpha2amylose, in %hich the glucoses are lin$ed together in straightchains, and amylopectin, in %hich the glucose chains are highlybranched ?xcept for the branch points of amylopectin, the glucosemonomers in starch are lin$ed via alpha312@84 glycosidic bonds, %hich,in the digestive tract of mammals, are hydrolyed by amylases

&ellulose is the other ma>or plant carbohydrate It is the ma>orconstituent of plant cell %alls, and more than half of the organic carbonon 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 toenymatically digest

.lycogen is the third large polymer of glucose and is the ma>or animal

storage carbohydrate #i$e starch, the glucose molecules in glycogenare lin$ed together by alpha312@84 glycosidic bonds



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The process of digestion produces glucose, amino acids, glycerol, and fattyacids 3see above4 The energy in glucose is used to produce AT* via thereactions of glycolysis, cellular respiration, and the electron transport system3see diagram belo%4 The body uses amino acids to construct proteins?xcess amino acids can be used to synthesie pyruvate, acetyl &oA, andalpha $etogluterate, %hich enters the -rebs cycle .lycerol and fatty acidscan be converted to pyruvate and Acetyl &oA and then enter cellularrespiration

Mouth&he%ing brea$s food into smaller particles so that chemical digestion canoccur faster

%n&'mes:Salivary amylasebrea$s starch 3a polysaccharide4 do%n to

maltose 3a disaccharide4

Bicarbonate ions in saliva act as buffers, maintaining a p+ bet%een 9uice contains sodium bicarbonate %hich neutralies the acidicmaterial from the stomach

Pacreatic amylasedigests starch to maltose

(rypsiandChymotrypsi digest proteins to peptides #i$e pepsin

3produced in the stomach4, they are specific for certain amino acids, notall of them They therefore produce peptides

Lipasedigests fats to glycerol and fatty acids


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LiverThe liver produces )ile%hich is stored in !all)ladderand sent to theduodenum through a ductBile emulsifies fats 3separates it into small droplets4 so they can mix %ith%ater and be acted upon by enymesthe" !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 processmaintains a constant glucose concentration in the blood 3614 Ifglycogen 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 Digestion1 +ast"in: The presence of food in the stomach stimulates specific

receptors %hich in turn stimulates endocrine cells in the stomach tosecrete the hormone !astriinto the circulatory system .astrinstimulates the stomach to secrete gastric >uice

! ec"etin: Secretin is produced by cells of the duodenumItCs production isstimulated by acid chymefrom stomachIt stimulates the pancreas

to produce sodiumbicarbonate, %hich neutralies the acidic chyme It also stimulates the liver tosecrete bile

5 choec'stoinin: &&- production is stimulated by the presenceof food in the duodenum It stimulates the gallbladder to release bile andthe pancreas to produce pancreatic enymes

8 +$, +ast"ic $nhibito"' ,e*tide:ood in the duodenum stimulatescertain endocrine cells to produce .I*


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


Small IntestineThe small intestine is approximately 5 m long #i$e the stomach, it containsnumerous ridges and furro%s In addition, there are numerous pro>ectionscalled villithat function to increase the surface area of the intestine Individualvillus cells have microvilli%hich greatly increase absorptive surface areaThe total absorptive surface area is eEuivalent to


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Summary of Digestive Enzymes

8he di)estive en&'mes in the tabe beo a"e s!mma"i&ed acco"din) tot'*e of food that the' di)est.

;;D TG*? ?7HG'? S;)&? *);D&TS

&A)B;+GD)AT?S Salivary amylase*ancreatic amylase'altase

Salivary glands*ancreasSmall intestine

'altose'altose.lucose

*);T?I7S *epsinTrypsin*eptidases

Stomach mucosa*ancreasIntestinal mucosa

*eptides*eptidesAmino acids

ATS #ipase *ancreas atty acids

and glycerol

8he tabe beo shos di)estive en&'mes )"o!*ed b' so!"ce of theen&'me.

S;)&? ?7HG'? ;;D *);D&T

';T+ 3salivaryglands4

Salivary amylase *olysaccharides 'altose

ST;'A&+ *epsin *roteins *eptides

*A7&)?AS *ancreaticamylaseTrypsin#ipase

*olysaccharides*roteinsats

'altose*eptidesatty acidsand glycerol

S'A## I7T?STI7? 'altase*eptidases

'altose*eptides

.lucoseAmino acids


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LECTURE 2 Thursday 29/9/2011

Digestion and Digestive Secretion from'outh and Stomach

The Mouth

Coplex !ood substan"es taken by anials ust be broken do#ninto siple$ soluble and di!!usible substan"es be!ore they "an be

absorbed into the body. %n the outh$ sali&ary glandsse"rete *+amylase,#hi"h digests star"h into sall segents o! ultiplesugarsand into the indi&idual soluble sugars.

'ali&ary glandsalso se"rete lysoye$ #hi"h kills ba"teriabut is not"lassi!ied as a digesti&e enye.

The 'toa"h

oodstu!!s entering the stoa"h ha&e been$ "rushed and redu"edin sie by asti"ation$ #ith sali&a. The stoa"h pro&ides four )asicfuctiosthat assist in the early stages o! digestion and prepare theingesta !or !urther pro"essing in the sall intestine*

1- %t ser&es as a short+term stora!e reservoir$ allo#ing a ratherlarge eal to be "onsued +ui"kly and dealt #ith o&er an extended

period.

2- %t is in the stoa"h that su)statial chemical ad e.ymaticdi!estio is iitiated, particularly of proteis-

3- ,igorous "ontra"tions o! gastri" sooth us"le ix and grind!oodstu!!s #ith gastri" se"retions$ resulting in li/uefactio offood$ a prere+uisite !or deli&ery o! the ingesta to the sallintestine.

4- -s !ood is li+ue!ied in the stoa"h$ it is slowly released itothe small itestie!or !urther pro"essing.


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http://en.wikipedia.org/wiki/Oral_cavityhttp://en.wikipedia.org/wiki/Salivary_glandshttp://en.wikipedia.org/wiki/Amylasehttp://en.wikipedia.org/wiki/Amylasehttp://en.wikipedia.org/wiki/Sugarhttp://en.wikipedia.org/wiki/Salivary_glandshttp://en.wikipedia.org/wiki/Lysozymehttp://en.wikipedia.org/wiki/Bacteriumhttp://en.wikipedia.org/wiki/Oral_cavityhttp://en.wikipedia.org/wiki/Salivary_glandshttp://en.wikipedia.org/wiki/Amylasehttp://en.wikipedia.org/wiki/Amylasehttp://en.wikipedia.org/wiki/Sugarhttp://en.wikipedia.org/wiki/Salivary_glandshttp://en.wikipedia.org/wiki/Lysozymehttp://en.wikipedia.org/wiki/Bacterium


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%! the lining o! the stoa"h is exained #ith a hand lens$ one "ansee that it is "o&ered #ith nuerous sall holes. These are theopenings o! gastri" pits #hi"h extend into the u"osa as straight andbran"hed tubules$ !oring gastri" glands.


our aor types o! se"retory epithelial "ells "o&er the sur!a"e o! thestoa"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" enye

/. $ cells* se"rete the horone gastrin


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$astric secretios

1. Mucosal Protection

Mu"us layer on gastri" sur!a"e !ors a u"osal barrier to daageagainst se&eral !ors o! potential inury to the gastri" u"osa.

1. - gel 0.2 thi"k 0 C5 20 protein2. '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 stiulated by a"etyl"holine !ro ner&e endings

/. -lso ri"h in bi"arbonate

a. C537"ontent "reates a 8i"ro7en&ironent8 around sur!a"e

"ells to pre&ent a"id daage

b. C537se"retion is inhibited by adrenergi" input (proinent in

stress)

2. Acid Secretion

ydro"hlori" a"id is se"reted !ro parietal "ells into the luen #hereit establishes an extreely a"idi" en&ironent. This a"id is iportant!or a"ti&ation o! pepsinogen and ina"ti&ation o! ingested

i"roorganiss su"h as ba"teria.2-1- Fuctio of $astric acid

1. To kill i"ro7organiss* (but . pylori sur&i&es by aking aonia(basi") !ro urea using urease).

2. to pro&ide the optial 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.


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/. stiulating duodenu to liberate se"retin

9. breaks do#n "onne"ti&e tissue in !ood


2-2-#echaism of !astric acid secretio

The hydrogen ion "on"entration in parietal "ell se"retions isroughly 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"retedagainst 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"haniss in the parietal "ell


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The key player in a"id se"retion is a :;


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= ydrogen ion is puped out o! the "ell$ into the luen$ in ex"hange!or potassiu through the a"tion o! the proton pup potassiu is thuse!!e"ti&ely re"y"led.

-""uulation o! osoti"ally7a"ti&e hydrogen ion in the "annali"ulusgenerates an osoti" gradient a"ross the ebrane that results inout#ard di!!usion o! #ater 7 the resulting gastri" ui"e is 1// MC1 and 1/ M


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istaines e!!e"t on the parietal "ell is to a"ti&ate adenylate "y"lase$ leadingto ele&ation o! intra"ellular "y"li" -MP "on"entrations and a"ti&ation o! protein

kinase - (Pinding o! a"etyl"holine and gastrin bothresult 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 stiulate release o! B% (gastri" inhibitorypolypeptide) and CC< ("hole"ystokinin)

'e&eral additional ediators ha&e been sho#n to result in gastri" a"idse"retion #hen in!used into anials and people$ in"luding e.g. "al"iu.Cal"iu siulates gastrin release. lt is un"lear #hether these

ole"ules ha&e a signi!i"ant physiologi" role in parietal "ell !un"tion.


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-lkaline tide during gastri" se"retion* 5#ing to se"reation o! a lageaount o! :as Cl$ there is surplus o! 57in the parietal "ell#hi"h is taken up not only by the C52to !or C53

7but also byother bu!!er systes o! parietal "ell initially and later by those o!

plasa.

42

2

4

POH

HPO

32

3

COH

HCO

acidLactic

Lactate

-ll tend to in"rease on the side o! the base i.e.*P5472$ C53

7and la"tate$ #ith the result that the p o! plasa is raised and analkaline urine is ex"reted !or soe hours !ollo#ing intake o! !oodand gastri" se"retion. This is kno#n as the alkaline tide.


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3. Proteases:

Pepsinogen$ an inactive ymogen, is secreted into gastric >uice fromboth mucous cells and chief cells ;nce secreted, pepsinogen isactivated by stomach acid into the a"ti&e protease pepsin$ %hich islargely responsible for the stomach(s ability to initiate digestion ofproteins, in young animals chief cells also secrete "hyosin (rennin)$a protease that coagulates mil$ protein allo%ing it to be retained morethan briefly in the stomach

Pepsinogens and Pepsins*epsinogens are secreted in a form such that the activationpeptide assumes a compact structure that occludes the active site;n exposure to an acidic 3p+ J 84 environment such as occurs in thelumen of the stomach, the activation peptide unfolds, allo%ing theactive site to clip it off, yielding mature, catalytically active pepsin

;ptimal activity of pepsins is at p+ of 1 to 5


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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 deonstrated thatse"retion is e!!e"ti&ely stiulated by agents that stiulate either o!t#o "onditions*

1 @le&ated intra"ellular le&els o! "y"li" -MP* exaples in"ludese"retin$ &asoa"ti&e intestinal peptide and epinephrine.

! @le&ated intra"ellular "al"iu* the prin"ipal ediatorsin&estigated in"lude a"etyl"holine and peptides o! thegastrin;"hole"ystokinin !aily

Pepsin #as dis"o&ered by Theodor '"h#ann in 139. %t #as the !irstanial enye to be dis"o&ered.

Chyosin (6ennin) and the Coagulation o! Milk

Chyosin$ kno#n also as rennin$ is a proteolyti" enye synthesiedby "hie! "ells in the stoa"h. %ts role in digestion is to "oagulate ilkin the stoa"h$ a pro"ess o! "onsiderable iportan"e in the &eryyoung anial. %! ilk #ere not "oagulated$ it #ould rapidly !lo#through the stoa"h and iss the opportunity !or initial digestion o! its

proteins.

Chyosin e!!i"iently "on&erts li+uid ilk to a seisolid like "ottage"heese$ allo#ing it to be retained !or longer periods in the stoa"h.Chyosin se"retion is axial during the !irst !e# days a!ter birth$

and de"lines therea!ter$ repla"ed in e!!e"t by se"retion o! pepsin asthe aor gastri" protease.

Prof. Dr. Hedef Dhar El-Yassin 201119


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Chyosin is se"reted as an ina"ti&e proenye "alled pro"hyosinthat$ like pepsin$ is a"ti&ated on exposure to a"id. Chyosin is alsosiilar to pepsin in being ost a"ti&e in a"idi" en&ironents$ #hi"hakes sense "onsidering its ission.

-side !ro its physiologi" role$ "hyosin is also a &ery iportantindustrial enye be"ause it is #idely used in "heese aking.

4. Hormones

The prin"iple horone se"reted !ro the gastri" epitheliu is gastrin$a peptide that is iportant in "ontrol o! a"id se"retion and gastri"otility. Bastrin is se"reted by B7"ells and released into the blood#here it tra&els to the parietal "ells to stiulate a"id se"retion$ and to@ntero"hroa!!in7Like (@CL) Cells to stiulate histaine se"retion.

The net result o! gastrin se"retion is in"reased a"id produ"tionthrough t#o e"haniss*

1. Dire"t stiulation o! the parietal "ells$

2. Tropi" a"tion on parietal "ells in"reasing their nuber.

?.>. in gastrinoa (Eollinger7@llison syndroe) in"reased produ"tiono! gastrin "auses hyperse"retion o! a"id #hi"h is not sube"t to noralinhibitory e"haniss.

A number of other enymes are secreted by gastric epithelial cells,

including a lipase and gelatinase ;ne secretory product ofconsiderable importance in man is intrinsic factor, a glycoproteinsecreted by parietal cells that is necessary for intestinal absorption ofvitamin B1!



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Intrinsic actor

%ntrinsi" !a"tor is a gly"oprotein se"reted by parietal (huans) o! thegastri" u"osa. %n huans$ it has an iportant role in the absorption o!&itain B1!("obalain) in the intestine$ and !ailure to produ"e orutilie intrinsi" !a"tor results in the "ondition perni"ious aneia.Fas a result o! an autoiune atta"k against parietal "ells F

Dietary &itain B1!is released !ro ingested proteins in thestoa"h through the a"tion o! pepsin and a"id. %t is rapidly boundby one o! t#o &itain B1!7binding proteins that are present in gastri"

ui"e at a"id p$ these binding proteins ha&e a greater a!!inity !orthe &itain than does intrinsi" !a"tor. %n the sall intestine

pan"reati" proteases digest the binding proteins$ releasing &itainB1!#hi"h then be"oes bound to intrinsi" !a"tor. inally$ there arere"eptors !or intrinsi" !a"tor on the ileal u"osa #hi"h bind the"oplex$ allo#ing &itain B1!to be absorbed into portal blood.

%n all aals$ &itain B1!is ne"essary !or aturation o! erythro"ytes$and a de!i"ien"y o! this &itain leads to de&elopent o! aneia.

'in"e e!!i"ient absorption o! &itain B1!in huans depends onintrinsi" !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 bindingand absorption o! the intrinsi" !a"tor7&itain >12"oplex (e.g. ilealdisease or rese"tion) "an result in this type o! aneia.

Abso"*tion in the tomach

The stoa"h absorbs &ery !e# substan"es$ although sall aountso! "ertain lipid7soluble "opounds "an be taken up$ in"ludingaspirin$ other non7steroidal anti7in!laatory drugs$ and ethanol.

?otably$ these substan"es are also #ell7re"ognied "auses o!gastri" irritation and their use (espe"ially o&eruse) is "oonlyasso"iated #ith de&elopent o! gastritis and gastri" ul"ers.



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LECTURE 3 Sunday 2/10/2011

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

he Pancreas

The pancreas plays a vital role in accomplishing the follo%ings:

K Acid must be Euic$ly and efficiently neutralied 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



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*ancreatic >uice is composed of t%o secretory products critical to proper

digestion: digestive enymes and bicarbonate The enymes are synthesied 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 synthesied 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 synthesied and pac$aged into secretory vesicles as

the inactive proenymes 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



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;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 enyme 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 to single amino acids Some

of the other proteases from the pancreas, for instance car)o4ypeptidase

3exopeptidase43This en1yme removes, one by one, theamino 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



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)- 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 enyme 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 enyme that hydrolyses starch to maltose 3a glucose2glucose

disaccharide4, as %ell as the trisaccharide maltotriose and small branchpoints fragments

called dextrins

d- 5ther Pan"reati" @nyes

In addition to the proteases, lipase and amylase, the pancreas produces a host of

other digestive enymes, including nucleases, gelatinase and elastase

!ceases These hydrolye ingested nucleic acids 3)7A and D7A4 into their

component nucleotides



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%astase: &uts peptide bonds next to small, uncharged side chains such as

those of alanine and serine


2. ;ica"bonate and


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The most important stimuli for pancreatic secretion come from three hormones secreted

by the enteric endocrine system:

K hoec'stoinin: This hormone is synthesied and secreted by enteric endocrinecells located in the duodenum Its secretion is strongly stimulated by the presence ofpartially digested proteins and fats in the small intestine As chyme floods into thesmall intestine, cholecysto$inin is released into blood and binds to receptors onpancreatic acinar cells, ordering them to secrete large Euantities of digestiveenymes It also stimulates the gallbladder to release bile and the pancreas toproduce pancreatic enymes

K ec"etin: This hormone is secreted in response to acid in the duodenum Thepredominant effect of secretin on the pancreas is to stimulate duct cells tosecrete %ater and bicarbonate As soon as this occurs, the enymes secreted bythe acinar cells are flushed out of the pancreas, through the pancreatic ductinto the duodenum It also stimulates the liver to secrete bile

K +ast"in: This hormone, %hich is very similar to cholecysto$inin, is secreted inlarge amounts by the stomach in response to gastric distention and irritation, inaddition to stimulating acid secretion by the parietal cell gastrin stimulatespancreatic acinar cells to secrete digestive enymes



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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 utiliation 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



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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:

;ie contains bie acids= hich a"e c"itica fo" di)estion and abso"*tion

of fats and fat-so!be vitamins in the sma intestine.

an' aste *"od!cts a"e eiminated f"om the bod' b' sec"etion into bie

and eimination 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 acidsand 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


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)ole of Bile Acids in at Digestion and Absorption

Bile salts are formed in the hepatocytes by a series of enymatic 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

enymes belonging to either monooxygenase or dehydrogenase enyme

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


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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 38ugated 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 theenterohepati"

"ir"ulation.


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?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 thanF6 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


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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 thesurface area of fat, ma$ing it available for digestion by lipases, %hich

cannot access the inside of lipid droplets

! Solubiliation and transport of lipids in an aEueous environment: Bile

acids are lipid carriers and are able to solubilie many lipids by

forming micelles 2 aggregates of lipids such as fatty acids, cholesterol

and monoglycerides 2 that remain suspended in %ater Bile acids arealso 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- CC #ri!i#a(

&i#e((ar #$n#en!ra!i$n

Prof.Dr H.D.El-Yassin

2011

34


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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 solubilie 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 ority of that is diverted into the

gallbladder for concentration 0hen chyme from an ingested meal enters thesmall 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:


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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


2011

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Detoxication in t!e "i#erDetoxication in t!e "i#er

The liver is one of the most important organs in the body %hen it comes todetoxifying or getting rid of foreign substances or toxins, especially from thegut

The liver detoxifies harmful substances by a complex series of chemicalreactions The role of these various enyme activities in the liver is toconvert !at solubletoxins into #ater solublesubstances that can beexcreted in the urine or the bile depending on the particular characteristicsof the end product 'any of the toxic chemicals that enter the body are fat2soluble, %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 solublechemicals have a high affinity for fat tissues and cell membranes, %hich arecomposed 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 removelarge toxins, synthesies and secretes bile full of cholesterol and other fat2soluble toxins, and enymatically disassembles un%anted chemicals



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This enymatic process usually occurs in t%o steps referred to as:

phase %and

phase %%

*hase I either directly neutralies a toxin, or modifies the toxic chemical toform activated intermediates %hich are then neutralied by one of more ofthe several phase II enyme systems

The level of exposure to environmental carcinogens varies %idely, as doesthe efficiency of the detoxification enymes, particularly phase II +ighlevels of exposure to carcinogens coupled %ith slo% detoxification enymessignificantly increases susceptibility to cancer


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,hase $ (etoxificationThis path%ay converts a toxic chemical into a less harmful chemical This isachieved by various chemical reactions 3such as oxidation, reduction and

hydrolysis4, and during this process free radicals are produced %hich, ifexcessive, can damage the liver cells Antioxidants reduce the damagecaused by these free radicals If antioxidants are lac$ing and toxin exposureis high, toxic chemicals become far more dangerous Some may beconverted from relatively harmless substances into potentially carcinogenicsubstancesThe effects of exposure to toxins varies from individual to individual Somepeople 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?#%>8?#%,450 ,450 @>+%A%@>+%A%>8%>8%

'onooxygenase 3mixed function oxidases4 incorporate one atom frommolecular oxygen into a substrate 3creating a hydroxyl group4, %ith theother atom being reduced to %ater In the "yto"hroe P4/0onooxygenase syste7AD*+ provides the reducing eEuivalentsreEuired by the series of reactions This system performs differentfunctions in t%o separate locations in cellsThe overall reaction catalyedby a "yto"hroe P4/0 enyeis:

#-? 2 A(,? ? #-? ?2 A(,

%here ) may be a steroid, drug or other chemical

1 #itochodrial System: the function of the mitochondrial"yto"hroe P4/0 onooxygenase systeis to participate in thehydroxylation of steroids, a process that ma$es theses hydrophobiccompounds more %ater soluble or example, in the steroidhormone producing tissues, such as placenta, ovaries, testes and

adrenal cortex, it is used to hydroxylate intermediates in theconversion of cholesterol to steroid hormones The liver uses thissystem in bile acid synthesis, and $idney uses it to hydroxylatvitamin !


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! #icrosomal System: An extremely important function the functionof the microsomal "yto"hroe P4/0 onooxygenase syste

found associated %ith the membranes of the endoplasmicreticulum 3particularly in the liver4 is the detoxification of foreigncompounds 3xenobiotics4 Theses include numerous drugs such asvaried pollutants as petroleum products, carcinogens andpesticides The "yto"hroe P4/0 onooxygenase systecan beused to hydroxylate theses toxins again using 7AD*+ as thesource of reducing eEuivalents The purpose of these modificationsis:

a-a- it may itself activate or deactivate a drug,

)-)- or ma$e a toxic compound more soluble, thus facilitating itsexcretion in the urine or feces reEuently, ho%ever, the ne%hydroxyl group %ill serve as a site for con>ugation %ith polarcompound, such as glucuronic acid, %hich %ill significantlyincrease the compound(s solubility

?xcessive amounts of toxic chemicals such as pesticides can disrupt the *28


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A significant side2effect of phase I detoxification is the production of !reeradi"alsas the toxins are transformed22for each molecule of toxinmetabolied by phase I, one molecule of free radical is generated 0ithout

adeEuate free radical defenses, every time the liver neutralies a toxinexposure, it is damaged by the free radicals produced

The most important antioxidant for neutraliing the free radicals produced inphase I is glutathione In the process of neutraliing free radicals, ho%ever,glutathione3.S+4 is oxidied to glutathione disul!ide3.SS.4 .lutathioneis reEuired for one of the $ey phase II detoxification processes 0hen highlevels of toxin exposure produce so many free radicals from phase Idetoxification that the glutathione is depleted, the phase II processesdependent upon glutathione stop, producing oxidative stress or liverdamage The toxins transformed into activated intermediates by phase I aresubstantially more reactive than the phase I toxins %ere nless Euic$lyremoved from the body by phase II detoxification mechanisms, they cancause %idespread problems, especially "ar"inogenesis Therefore, the rateat %hich phase I produces activated intermediates must be balanced by therate at %hich phase II finishes their processing *eople %ith a very activephase I detoxification system coupled %ith slo% or inactive phase IIenymes are termedpathologi"al detoxi!iers These people suffer unusuallysevere toxic reactions to environmental poisons

An efficient liver detoxification system is vital to health and in order tosupport this process it is essential that many $ey nutrients are included inthe diet /itamins and minerals O particularly the B vitamins O play a ma>orrole, acting as cofactors for many enyme systems including those of liverdetoxification Depletion of vitamin & may also impair the detoxificationprocess vitamin & also prevents free radical formation /itamin ? andselenium are cofactors for glutathione peroxidase activity as %ell as beingpo%erful antioxidants ;ther nutrients %hich play vital roles in the *hase IIpath%ay include amino acids glycine, cysteine, glutamine, methionine,

taurine, glutamic acid and aspartic acid .rapefruit >uice, %hich containsnaringenin$slo%s do%n *hase I enyme activity

As %ith all enymes, the cytochrome *8


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,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 toxicchemical or drug This ma$es the toxin or drug %ater2soluble, so it can thenbe excreted from the body via %atery fluids such as bile or urine Individualxenobiotics 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>ugation5 'ethylation8 Sulfation


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.lutathione is also an important antioxidant This combination ofdetoxification and free radical protection, results in glutathione being one ofthe 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 beproduced or absorbed from the diet This results in increased susceptibilityto toxin2induced diseases, such as cancer, especially if phase Idetoxification system is highly active

A deficiency can be induced either by diseases that increase the need forglutathione, deficiencies of the nutrients needed for synthesis, or diseasesthat inhibit its formation .lutathione is available through t%o routes: dietand synthesis Dietary glutathione 3found in fresh fruits and vegetables,

coo$ed fish, and meat4 is absorbed %ell by the intestines and does notappear to be affected by the digestive processes Dietary glutathione infoods appears to be efficiently absorbed into the blood

2. Amino acid conj!)ationSeveral amino acids 3glyu"ine$ taurine$ glutaine$ arginine, and ornithine4are used to combine %ith and neutralie toxins ;f these, glycine is themost commonly utilied in phase II amino acid detoxification*atients suffering from hepatitis, alcoholic liver disorders, carcinomas,chronic arthritis, hypothyroidism, toxemia of pregnancy, and excessivechemical exposure are commonly found to have a poorly functioning aminoacid con>ugation system?ven in normal adults, a %ide variation exists in the activity of the glycinecon>ugation path%ay This is due not only to genetic variation, but also tothe availability of glycine in the liver .lycine, and the other amino acidsused for con>ugation, become deficient on a lo%2protein diet and %henchronic exposure to toxins results in depletion

3. eth'ation

'ethylation involves con>ugating ethyl groupsto toxins'ost of the methyl groups used for detoxification comes from '7adenosylethionine3SA'4 SA' is synthesied from the amino acidmethionine, a process %hich reEuires the nutrients choline, the active formof B1! 77ethyl "obalain, and the active form of folic acid 22/7ethyltetrahydro!olate 'ethionine is a ma>or source of numerous sulfur2containing compounds, including the amino acids cysteine and taurine



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4. !fationSulfation is the con>ugation of toxins %ith sulfur2containing compounds Thesulfation system is important for detoxifying several drugs, food additives,

and, especially, toxins from intestinal bacteria and the environment Inaddition to environmental toxins, sulfation is also used to detoxify somenormal body chemicals and is the main path%ay for the elimination ofsteroid and thyroid hormones Since sulfation is also the primary route forthe elimination of neurotransmitters, dysfunction in this system maycontribute to the development of some nervous system disorders'any factors influence the activity of sulfate con>ugation or example, adiet 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 thebody eliminates sulfa drugs This system appears to be especially sensitiveto genetic variation, %ith those having a poor acetylation system being farmore 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%nthat 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 enymes produced by pathologicalbacteria and cause toxins to be reabsorbed increasing toxicity 'any of thecommonly prescribed drugs are detoxified through this path%ay It alsohelps to detoxify aspirin, menthol, vanillin 3synthetic vanilla4, food additivessuch as benoates, and some hormones

!foxidationSulfoxidation is the process by %hich the sulfur2containing molecules indrugs and foods are metabolied It is also the process by %hich the bodyeliminates the sulfite food additives used to preserve many foods and

drugs 7ormally, the enyme sul!ite oxidase (olybdenudependentenye)metabolies sul!itesto safer sul!ates, %hich are thenexcreted 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 moresensitive to sulfur2containing drugs and foods containing sulfur or sulfiteadditives

Le#!ure 5 Thursday 6/10/2011



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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 )reain d$n (are su*ra&$(e#u(ar area!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 ines!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 area!es are e*$sed !$*an#rea!i# eny&esand)i(e

hi#h ena)(es dies!i$n !$ &$(e#u(es #a*a)(e $r a(&$s! #a*a)(e $% )ein a)s$r)ed. The %ina(

s!aes $% dies!i$n $##ur $n !he sur%a#e $% !he s&a(( in!es!ina( e*i!he(iu&.

The ne! e%%e#! $% *assae !hr$uh !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 $rani# &$(e#u(es

in#(udin (u#$se a&in$ a#ids and %a!!y a#ids. Thr$uh !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 thedigestive 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 distinctprocesses establish an osmotic gradient that pulls %ater into the lumen of theintestine:

1. $nc"eases in !mina osmotic *"ess!"e "es!tin) f"om inf!x anddi)estion of foodst!ffs: 8he ch'me that foods into the intestine f"om thestomach t'*ica' is not h'*e"osmotic= b!t as its mac"omoec!a"com*onents a"e di)ested= osmoa"it' of that so!tion inc"easesd"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 aregenerated, each of %hich is as osmotically active as the original starch molecule



2011

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http://www.vivo.colostate.edu/hbooks/pathphys/digestion/pancreas/exocrine.htmlhttp://www.vivo.colostate.edu/hbooks/pathphys/digestion/liver/bile.htmlhttp://www.vivo.colostate.edu/hbooks/pathphys/digestion/pancreas/exocrine.htmlhttp://www.vivo.colostate.edu/hbooks/pathphys/digestion/liver/bile.html


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Thus, as digestion proceeds lumenal osmolarity increases dramatically and %ater ispulled into the lumen Then, as the osmotically active molecules 3maltose, glucose,amino acids4 are absorbed, osmolarity of the intestinal contents decreases and %atercan be absorbed

2. "'*t ces active' sec"ete eect"o'tes= eadin) to ate" sec"etion: 8hea*ica o" !mena memb"ane of c"'*t e*itheia ces contain an ionchanne of immense medica si)nificance - a cyclic #P+depedetchloride chael ow also as the cystic fi)rosis trasmem)raecoductace re!ulator or CF(R-!tations in the )ene fo" this ionchanne "es!t in the disease c'stic fib"osis. 8his channe is "es*onsibefo" sec"etion of ate" b' the fooin) ste*s:

1 &hloride ions enter the crypt epithelial cell by cotransport %ithsodium and potassium sodium is pumped bac$ out via sodiumpumps, and potassium is exported via a number of channels

! Activation of adenylyl cyclaseby a number of so2calledsecretagogues leads to generation of cyclic A'*

5 ?levated intracellular concentrations of cA'* in crypt cells activatethe &T), resulting in secretion of chloride ions into the lumen

8 Accumulation of negatively2charged chloride anions in the cryptcreates an electric potential that attracts sodium, pulling it into thelumen, apparently across tight >unctions 2 the net result is secretionof 7a&l

unction and %ater is dra%n into the lumen

Le#!ure

5

Thursday 6/10/2011

$$A ##%A8$

Cystic fibrosis


2011

46
http://www.vivo.colostate.edu/hbooks/molecules/sodium_pump.htmlhttp://www.vivo.colostate.edu/hbooks/molecules/sodium_pump.htmlhttp://www.vivo.colostate.edu/hbooks/molecules/cyclase.htmlhttp://www.vivo.colostate.edu/hbooks/molecules/sodium_pump.htmlhttp://www.vivo.colostate.edu/hbooks/molecules/sodium_pump.htmlhttp://www.vivo.colostate.edu/hbooks/molecules/cyclase.html


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,)n$r&a( a#!i"a!i$n $% !he #,'de*enden! #h($ride #hanne( CTR 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 ea&*(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 thesmall intestineTo remain viable, all cells are reEuired to maintain a lo% intracellularconcentration of sodium In polaried epithelial cells li$e enterocytes, lo% intracellularsodium is maintained by a large number of 7a=M-=AT*ases 2 so2called sodiumpumps2 embedded in the basolateral membrane These pumps export 5 sodium ionsfrom 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 arereEuired to understand absorption in the small intestine Also, dietary sources ofprotein, 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


1 Abso"*tion of


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The s&a(( in!es!ine &us! a)s$r) &assi"e +uan!i!ies $% a!er. , n$r&a( *ers$n aes in r$uh(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 ines!a en!ers !he (are in!es!ine a**r$i&a!e(y 80; $% !his %(uid has )eena)s$r)ed.


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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 sodiumusing the same transporter ructose enters the cell from the intestinal lumen via

facilitated diffusion through another transporter)sorptio of $lucose ad other #oosaccharides&(rasport across the testial 7pitheliumAbsorption of glucose entails transport from the intestinal lumen, across theepithelium and into blood The transporter that carries glucose and galactose into theenterocyte is the sodium2dependent hexose transporter, $no%n more formally as+B8-1.As the name indicates, this molecule transports both glucose and sodiumion into the cell and in fact, %ill not transport either aloneThe essence of transport by the sodium2dependent hexose transporter involves aseries of conformational changes induced by binding and release of sodium andglucose, and can be summaried as follo%s:

1 the transporter is initially oriented facing into the lumen 2 at this point it is capable ofbinding sodium, but not glucose

! sodium binds, inducing a conformational change that opens the glucose2bindingpoc$et

5 glucose binds and the transporter reorients in the membrane such that the poc$etsholding sodium and glucose are moved inside the cell

8 sodium dissociates into the cytoplasm, causing glucose binding to destabilie


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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 eny&e $r se"era( eny&es %$r a "arie!y $% reas$ns ene!i#

de%e#! *hysi$($i#a( de#(ine i!h ae $r !he resu(! $% :in@uries: !$ !he &u#$sa. % !he

disa##haridases (a#!ase is !he &$s! #$&&$n eny&e i!h an a)s$(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$(ye(a#!$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 $%

ines!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$(yed

durin !he %er&en!a!i$n *r$#ess $% &ain y$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 eny&e (a#!ase is

#$&&er#ia((y a"ai(a)(e !$ *re!rea! &i( s$ !ha! !he (a#!$se is hydr$(yed.

3 Abso"*tion of Amino Acids and ,e*tidesDietary 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 andpancreatic proteases The brush border of the small intestine is eEuipped %ith afamily of peptidases #i$e lactase and maltase, these peptidases are integralmembrane proteins rather than soluble enymes They function to further thehydrolysis of lumenal peptides, converting them to free amino acids and very smallpeptides These end products of digestion, formed on the surface of the enterocyte,are ready for absorption

a8 )sorptio of mio cidsThe &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$na( #hane !ha! du&*s s$diu& and !he a&in$ a#id

in!$ !he #y!$*(as& %$(($ed )y i!s re$rien!a!i$n )a# !$ !he $riina( %$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 (ie !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.


CI!ICA C"##EA$I"!

!eutral Amino Aciduria %&artnup Disease'


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Trans*$r! %un#!i$ns (ie eny&a!i# %un#!i$ns are su)@e#! !$ &$di%i#a!i$n )y &u!a!i$ns. ,n

ea&*(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$& !he de%e#! as %irs! re#$nied. The

disease is #hara#!eried )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$i&a( !u)u(e !hr$uh !he u(!ra%i(!ra!e !he ina)i(i!y !$ rea)s$r) a&in$ a#ids &ani%es!si!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((ara(ie %ea!ures are e*(ained )y a de%i#ien#y $% !ry*!$*han hi#h ser"es as

*re#urs$r %$r ni#$!ina&ide. ?n"es!ia!i$ns $% *a!ien!s i!h >ar!nu* disease re"ea(ed !he

eis!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!hay %$r a)s$r*!i$n $% *r$!ein dies!i$n *r$du#!s

)8 )sorptio of PeptidesThere is "ir!ua((y n$ a)s$r*!i$n $% *e*!ides ($ner !han %$ur a&in$ a#ids. >$e"er !here is

a)undan! a)s$r*!i$n $% di and !ri*e*!ides in !he s&a(( in!es!ine. These s&a(( *e*!ides area)s$r)ed in!$ !he s&a(( in!es!ina( e*i!he(ia( #e(( )y #$!rans*$r! i!h > Ai$ns "ia a !rans*$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 dies!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 Proteis

,)s$r*!i$n $% in!a#! *r$!eins $##urs $n(y in a %e #ir#u&s!an#es.


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Dies!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"oC (+= diac')'ce"oC += monoac')'ce"oC A= fatt' a

cid

$$A ##%A8$

A- -i*o*"oteinemia

A2b2lipoproteinemia is an autosomal recessive disorder characteried 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 isassociated %ith severe malabsorption of triacylglycerol and lipid2soluble vitamins 3especiallytocopherol and vitamin ?4 and accumulation of apo B in enterocytes and hepatocytes Thedefect does not appear to involve the gene for apo B, but rather one of several proteins involvedin processing of apo B in liver and intestinal mucosa, or in assembly and secretion oftriacylglycerol2rich lipoproteins, that is, chylomicrons and /#D#s from these tissues,respectively


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5 Abso"*tion of ine"as and etas

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& andir$n de%i#ien#ies $% hi#h are sini%i#an! hea(!h

*r$)(e&s !hr$uh$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&s-

1.!cti"e# transcellular absorption$##urs $n(y in !hedu$denu& hen #a(#iu& in!ae 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 hih. ?n !his #ase

i$nied #a(#iu& di%%uses !hr$uh !ih! @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 $n ha"in hiher #$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$rani# *h$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 reu(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$nde%i#ien#y dis$rders su#h as

ane&ia. n !he $!her hand e#essi"e ir$n is !$i# )e#ause

&a&&a(s d$ n$! ha"e a *hysi$($i# *a!hay %$r i!s

e(i&ina!i$n.


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?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 acidicen"ir$n&en!.

erri# ir$n eAAA in !he du$dena( (u&en is redu#ed !$ i!s %err$us %$r& !hr$uh !he a#!i$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*$r!er DT1. This !rans*$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!hays-

%ron abundan"e states: iron %ithin the enterocyte is trapped by incorporationintoferritinand hence, not transported into blood 0hen the enterocyte diesand is shed, this iron is lost

%ron liiting states: iron is exported out of the enterocyte via a transporter3ferroportin4 located in the basolateral membrane It then binds to the iron2carrier transferrin for transport throughout the body

d8 Copper

There a**ear !$ )e !$ *r$#esses res*$nsi)(e %$r #$**er a)s$r*!i$n-

i a ra*id ($ #a*a#i!y sys!e& and

ii a s($er hih #a*a#i!y sys!e& hi#h &ay )e si&i(ar !$ !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 enes disease.

, nu&)er $% die!ary %a#!$rs ha"e )een sh$n !$ in%(uen#e #$**er a)s$r*!i$n. $r ea&*(e

e#essi"e die!ary in!ae $% ei!her in# $r &$(y)denu& #an indu#e se#$ndary #$**er

de%i#ien#y s!a!es.

e8 9ic

Bin# h$&e$s!asis is (are(y reu(a!ed )y i!s u*!ae and ($ss !hr$uh !he s&a(( in!es!ine.

,(!h$uh 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!eri#h die!s is !h$uh! res*$nsi)(e %$r a #$nsidera)(e %ra#!i$n $% hu&an in#

de%i#ien#ies.


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Le#!ure 6 Sunday 9/10/2011

ec"etion and Abso"*tion in the a")e

$ntestineThe 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 eect"o'tes f"om in)esta: By the time ingesta

reaches the terminal ileum, roughly F6 of its %ater has been absorbed, butconsiderable %ater and electrolytes li$e sodium and chloride remain and mustbe 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 enymes capable of digesting many ofmolecules that to vertebrates are indigestible, cellulose being a premierexample The extent and benefit of fermentation also varies greatly amongspecies

Abso"*tion= ec"etion and o"mation of eces in the a")e $ntestine1 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 mechanismresponsible for generating this osmotic pressure is essentially identical to %hat %asseen in the small intestine2 sodium ions are transported from the lumen across the

epithelium by virtue of the epithelial cells having very active sodium pumps on theirbasolateral membranes and a means of absorbing sodium through their lumenalmembranes The colonic epithelium is actually more efficient at absorbing %ater thanthe small intestine and sodium absorption in the colon is enhanced by the hormonealdosterone&hloride is absorbed by exchange %ith bicarbonate The resulting secretion ofbicarbonate ions into the lumen aids in neutraliation of the acids generated bymicrobial fermentation in the large gut


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$de( %$r e(e#!r$eni# or endproducts of microbial digestion of cellulose and other carbohydrates are volatile fattyacids, lactic acid, methane, hydrogen and carbon dioxide ermentation is thus thema>or source of intestinal gas /olatile fatty acids 3acetic, proprionic and butyricacids4 generated from fermentation can be absorbed by diffusion in the colon

Synthesis of vitamin -by colonic bacteria provides a valuable supplement to dietarysources and ma$es clinical vitamin - deficiency rare Similarly, formation of Bvitamins by the microbial flora in the large intestine is useful to many animals Theyare not absorbed in the large intestine, but are present in feces


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$ntestina +as ,"od!ctionA considerable amount of gas is present in the gastrointestinal contents of allanimalsive 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 isdue 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 bicarbonateions 3principally from gastric and pancreatic secretions4 leads to generation of&;! The amount of gas generated by this path%ay is not great, because thelumenal contents do not contain carbonic anhydrase and the dissociation of+!&;5is thus Euite slo% Additionally, most of the &;! produced in this %ay is

absorbed into blood(he secodand much more productive source of gas is fermentation bycolonic bacteria 'icrobes appear to be the sole source of all of the hydrogenand methane produced in the intestine A variety of fruits and vegetablescontain polysaccharides that are not digested in the small intestine and lead tovoluminous gas production by microbes Indeed, the primary medicaltreatment for excessive gas production is dietary manipulation to eliminatefoodstuffs that the individual cannot digest and absorb

8he +ast"ointestina ;a""ie"

The gastrointestinal mucosa forms a barrier bet%een the body and alumenal environment %hich not only contains nutrients, but is loaded %ithpotentially hostile microorganisms and toxins The challenge is to allo%efficient transport of nutrients across the epithelium %hile rigorouslyexcluding passage of harmful molecules and organisms into the animalThe exclusionary properties of the gastric and intestinal mucosa arereferred to as the "gastrointestinal barrier8.

The gastrointestinal barrier is often discussed as having t%ocomponents:

1 The intrinsic barrier is composed of the epithelial cells lining thedigestive 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 theepithelial cells and maintain their barrier function

a 'ucus and Bicarbonate


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The entire gastrointestinal epithelium is coated %ith mucus, %hich servesan important role in mitigating shear stresses on the epithelium andcontributes to barrier function in several %ays The abundant

carbohydrates on mucin molecules bind to bacteria, %hich aids inpreventing epithelial coloniation and, by causing aggregation,accelerates clearance Diffusion of hydrophilic molecules is considerablylo%er in mucus than in aEueous solution, %hich is thought to retarddiffusion of a variety of damaging chemicals, including gastric acid, to theepithelial surface

b +ormones and &yto$ines7ormal proliferation of gastric and intestinal epithelial cells, as %ell asproliferation in response to such in>ury as ulceration, is $no%n to beaffected by a large number of endocrine and paracrine factors Several ofthe enteric hormonesare $no%n to enhance rates of proliferationDifferent forms of in>ury to the epithelium can lead to either enhanced orsuppressed rates of cell proliferation*rostaglandins, particularly prostaglandin ?! and prostacyclin, have longbeen $no%n to have "cytoprotective" effects on the gastrointestinalepithelium A common clinical correlate in many mammals is that use ofaspirin and other non2steroidal antiinflammatory drugs 37

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

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