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XENOBIOTICS AND ITSMETABOLISM

Group 7

Nagpiing, JeanNoche, Reginald Bruce

Orellana, Joi MariePanis, Moises Laureano

Pareja, John PaulPeralta, Kathy

1F


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DEFINITION

Xen obioticschemical which is found in an organism but

which is not normally produced or expected tobe present in it

Greek words ( xenos

) = foreigner, stranger and (bios, vios ) = life.


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PR INCIPAL CLASS ES

Drugsantibiotics,analgesics likeacetaminophen,cardiac drugs


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PR INCIPAL CLASS ES

Ca rci n og en sFood Dyes, Preservatives,Nitrosamines, Alcohol, Artificial

Sweeteners


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PR INCIPAL CLASS ES

Env iro nmen tal P o llut an ts and Chem ic al s

>200 ,00 manufacturedenvironmentalchemical/pollutantsin existence


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S IGNIFIC A NCE

Studying these Xenobiotics are significant inman because these Xenobiotics can enter thebody and may have different effects onhuman systems. Xenobiotics can be a toxicmetabolite which can lead to toxicity.It can be an active metabolite that can alter or

enhance activity or it can also lead to toxicity.It can be an inactive metabolite that leads toloss of activity and it can be a reversiblemetabolite that results to prolonged activity.


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XENOBIOTIC A BS ORP TION

XENOBIOTIC S

oral

topical

inhalation

IM, SC,ID

IV BLOOD

INTESTINES

SKIN

MEMBRANES

LUNGS


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EXC R ETION


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XENOBIOTIC S MET A BO L IS M

Mechanism of elimination of foreign andundesirable compounds from the body

Metabolized by biotransformation or detoxification reaction

Site of metabolism = Liver


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XENOBIOTIC S MET A BO L IS M

Phase 1

Phase 2

2 PHASES


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P ha s e Ivariety of enzymes actto introduce reactiveand polar groups intoxenobiotics substrates

functionalization

Catalyzed by membersof a class of enzymesreferred to as monooxygenases or cytochrome 45 0


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P ha s e 1Hydr ox ylati on

- major reaction involved in phase 1

RH + O2 + NA DPH + H R- OH +H 20 + NA DP

Cytochrome P45 0

Lipophillic toxicant Hydrophillic molecule


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P ha s e 1C yt och r ome P450

- Located in the Smooth Endoplasmic Reticulum or in the Mitochondria- monooxygenase- one atom of oxygen enters R -OH and one atomenters H 20

RH + O2 + NA DPH + H R- OH +H 20 + NA DP


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R- OH +H 20 + NA DP

Excretable Form


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Othe r Enzyme s

Amine oxydase

Amidases

AlcoholDehydrogenase

Epoxide Hydratase

Esterases


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P ha s e 2Phase I derivatives aremade more polar (Water soluble ) throughConjugation Reaction

Includes 5 importantreaction

GlucorinadationSulfationConjugation with

Glutathione AcetylationMethylation


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PHAS E 2 R EA CTION S

1. Glucoro n ida tio nConjugation with Glucoronic AcidGlucoronyl donor: UDP -Glucoronic acidCatalyst: Glucoronyl Transferase ( ER andcytosol )

Aniline, phenols, 2- acetyl Aminoflourine,benzoic Acid, many steroids


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Glucoro n ida tio n

Glucoronidation of xenobiotics


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2. S u lfa tio nConjugation with sulfatePAPS Adenosine 3 - Phosphate -5

phosphosulfate (Active sulfate ) sulfate donor Alcohols, Aralymine, and Phenols


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3. Me thyla tio nTransfer of the methyl group to theXenobioticMethyl Group Donor: S - AdenosylMethionnine

Catalyst: Methyl Transferase


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P OLAR

4. A c e tyla tio nTransfer of the Acetyl Group to the Xenobiotics

Acetyl Group Donor: Acetyl CoA (Active Acetate )

Catalyst: Acetyl TransferaseSubject to Acetylation: ISONIAZID

X + A c e tylC o A A c e tyl -X + Co A


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PHAS E 2 R EA CTION S5. Glut a th io ne Co nj ug a tio n

Most potentially toxic electrophillic xenobiotics(carcinogens ) are conjugated to Glutathione

Conjugates are excreted in the bile andconverted into cysteine and mercapturicconjugates in the intestines and kidneysCatalyst: Glutathione S -transferase

R + G SH R S- G

xen obiotic me rc a pturic a ci d


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Glutathione

Tripeptide consisting of glutamic acid,

cysteine and glycineDecomposition of potentially toxichydrogen peroxide in the reaction

catalyzed by glutathione peroxidase


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Cy toc h ro me p45 0

responsible for the hydroxylation on phase 1 of xenobiotic metabolism.can bre reffered as monooxygenase most versatile catalyst

Can render substrates which are generally andinitially lipophilic to more hydrophilic by hydroxylation.Enzymes that use iron to oxidize things, often as partof the body's strategy to dispose of potentially harmful

substances by making them more water -soluble.Exhibits a distinct peak at 45 0nm when chemicallyreduced and exposed to carbon monoxide.H yd rox yla tio n chief reaction involved in phase 1.


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Cha r a ct e ristics

i. Large number of isoforms about (15 0)ii. Hemoprotein like hemoglobiniii. Widely distributed across species

iv. Microsomal found in the smoothendoplasmic reticulum, mostly in theliver

v. NADPH , not NADH is involved in thereaction mechanism of cytochromep45 0

vi. Lipids are important component of cytochrome p45 0


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Factors affecting Xenobiotics

MetabolismGene tic fa ctors, a g e and s e x


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due to difference in the activities of different enzymes.

Metabolism slowly in neonates andelderly.

Diet and intake of different nutrients


Metabolism


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Metabolism

Intake of various

xenobiotics(Phenobarbital ) can cause enzyme

induction .


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Pathological state . Disease involving gut and liver.

- Metabolites of certain xeonobiotics caneither stimulate or inhibit.


Metabolism


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THA NK YOU!


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References:

http://www.slideshare.net/noelmd/xenobiotic -metabolism -282 5134Murray L.K. et al: HarpersIllustratedBiochemistry.McGraw Hill; 2006

http://en.wikipedia.org/wiki/Xenobiotichttp://www.metabolismsite.com/metabolism/metabolism -xenobiotics.htmlhttp://www.ispub.com/journal/the_internet_jour

nal_of_nutrition_and_wellness/volume_7_number_1_ 21/article_printable/absorption_and_metabolism_of_xenobiotics_an_overview.html

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