XENOBIOTICSXENOBIOTICS

The Metabolism ofThe Metabolism of

Reported by Group III, 1-C2

What are Xenobiotics?What are Xenobiotics?

A compound that is to the body.A compound that is to the body.

Xeno =

foreign “stranger”     • may be natural or synthetic     • may be harmful or safe

EXAMPLES OF CARCINOGENIC XENOBIOTICS • Food components methyl glyoxal (coffee) • Food contaminants aflatoxin B1 • Cigarette smoke  • Industrial (occupational)dibromoethane • Industrial (effluent) vinyl chloride

•Cyanide is one example which is toxic at very low levels

Principal Classes of XenobioticsPrincipal Classes of Xenobiotics

DrugsDrugs

Chemical carcinogensChemical carcinogens

PCB’sPCB’s

InsecticidesInsecticides

There are 200,000 of theseThere are 200,000 of these

Most synthetic materialsMost synthetic materials

How does the body handle them?How does the body handle them?

For convenience, the metabolism of For convenience, the metabolism of xenobiotics is divided into xenobiotics is divided into 2 phases2 phases

There are approximately There are approximately 30 different 30 different enzymes that catalyze xenobiotic enzymes that catalyze xenobiotic compoundscompounds

2 phases2 phases

2 phases2 phases

1. Phase 1

::

•Most common reaction: hydroxylation

•Some enzymes: monooxygenases microsomal cytochrome-

P450s

•Most common reactions: conjugation

methylation

•Enzymes: transferases

2. Phase 2

Phase 1Phase 1Mainly hydroxylation reactionsMainly hydroxylation reactions

Enzyme: Microsomal Cytochromes P450sEnzyme: Microsomal Cytochromes P450s

Purpose: Purpose: 1. Make the toxin more water-soluble1. Make the toxin more water-soluble2. Sometimes deactivates the toxin2. Sometimes deactivates the toxin

Phase 1:Phase 1:

Microsomal cytochrome P450sMicrosomal cytochrome P450s Large number of isoformsLarge number of isoforms All contains hemeAll contains heme Has a special nomenclature:Has a special nomenclature:

CYP Family Subfamily Specific #

CYPs with >40%

similarity

CYPs with >55%

similarity

CYPs with >100% (exact)

similarity

2 C 9

Phase 1:Phase 1:

CYP 2 C 9

= A cytochrome that metabolizes warfarin

Phase 1:Phase 1:

Microsomal cytochrome P450sMicrosomal cytochrome P450s Large number of isoformsLarge number of isoforms All contains hemeAll contains heme Has a special nomenclature:Has a special nomenclature: Plenty in liver (in the SER)Plenty in liver (in the SER) Differs from the mitochondrial cytochrome P450Differs from the mitochondrial cytochrome P450 Has lipid components (primarily lecithin)Has lipid components (primarily lecithin) Inducible (CYP2C9)Inducible (CYP2C9) Some exhibit polymorphismSome exhibit polymorphism Rarely, some contribute to cancer formationRarely, some contribute to cancer formation

Phase 1:Phase 1:

Microsomal cytochrome P450sMicrosomal cytochrome P450s Large number of isoformsLarge number of isoforms All contains hemeAll contains heme Has a special nomenclature:Has a special nomenclature: Plenty in liver (in the SER)Plenty in liver (in the SER) Differs from the mitochondrial cytochrome P450Differs from the mitochondrial cytochrome P450 Has lipid components (primarily lecithin)Has lipid components (primarily lecithin) Inducible (CYP2C9)Inducible (CYP2C9) Some exhibit polymorphismSome exhibit polymorphism Rarely, some contribute to cancer formationRarely, some contribute to cancer formation

Inducible (CYP2C9)Inducible (CYP2C9) Some exhibit polymorphismSome exhibit polymorphism Rarely, some contribute to cancer formationRarely, some contribute to cancer formation

Inducible (CYP2C9)Inducible (CYP2C9)

Phase 1:Phase 1: Inducible (CYP2C9)Inducible (CYP2C9)

Q: If you give phenobarbital to a patient who is dependent on warfarin, you have to adjust (higher) the dose of the latter or risk bleeding. Why?

A: CYP2C9 , which metabolizes (inactivates) warfarin is induced by phenobarbital.

Q: Drinking along with smoking increases risk of cancer than smoking all by itself. Why?

A: CYP2E1, which is induced by ethanol (in liquor) is one of the cytochromes that contribute to the activation of procarcinogens found in tobacco smoke.

Phase 1:Phase 1:

Microsomal cytochrome P450sMicrosomal cytochrome P450s Large number of isoformsLarge number of isoforms All contains hemeAll contains heme Has a special nomenclature:Has a special nomenclature: Plenty in liver (in the SER)Plenty in liver (in the SER) Differs from the mitochondrial cytochrome P450Differs from the mitochondrial cytochrome P450 Has lipid components (primarily lecithin)Has lipid components (primarily lecithin) Inducible (CYP2C9)Inducible (CYP2C9) Some exhibit polymorphismSome exhibit polymorphism Rarely, some contribute to cancer formationRarely, some contribute to cancer formation

Phase 1:Phase 1:

Rarely, some contribute to cancer formationRarely, some contribute to cancer formation

An isoform of cytochrome P450 metabolize inactive PAHs (polycyclic aromatic hydrocarbons) into active carcinogens

PAHs are abundant in cigarette smoke

Smokers have increased levels of CYP1A1 in their cells than non-smokers.

CYP2E1 is induced by ethanol.

CYP1A1, CYP2E1:

Phase 1:Phase 1:

Microsomal cytochrome P450sMicrosomal cytochrome P450s Large number of isoformsLarge number of isoforms All contains hemeAll contains heme Has a special nomenclature:Has a special nomenclature: Plenty in liver (in the SER)Plenty in liver (in the SER) Differs from the mitochondrial cytochrome P450Differs from the mitochondrial cytochrome P450 Has lipid components (primarily lecithin)Has lipid components (primarily lecithin) Inducible (CYP2C9)Inducible (CYP2C9) Some exhibit polymorphismSome exhibit polymorphism Rarely, some contribute to cancer formationRarely, some contribute to cancer formation

Phase 1:Phase 1:

Some exhibit polymorphismSome exhibit polymorphism

CYP2D6CYP2D6 is involved in the metabolism of debrisoquin (antihypertensive drug) and sparteine (antiarrhythmic and oxytocic drug)

Polymorphisms (many different forms of CYP2D6 in the same medium) contribute to the lower the overall activity of the enzyme.

This is because some of the “variant forms” have low catalytic activity which pulls the overall activity down.

The poor catalysis of debrisoquin and sparteine allows them to stay and accumulate in the body and cause toxicity.

Polymorphisms and differences between enzyme structure between individuals is genetic

Phase 2Phase 2Conjugation reactionsConjugation reactionsEnzyme: TransferasesEnzyme: Transferases

Purpose: Make the toxin further water-Purpose: Make the toxin further water-soluble for excretionsoluble for excretion

Processing of XenobioticsProcessing of XenobioticsXenobioticXenobiotic

Reactive MetaboliteReactive Metabolite

Nontoxic MetaboliteNontoxic Metabolite

Cell injuryCell injury

HaptenHapten

MutationMutation

Antibody reaction

Antibody reaction

CancerCancer

OutOut

Phase 2:Phase 2:

Conjugation Conjugation RxnRxn

EnzymeEnzyme DonorDonor Examples of Xenobiotic Examples of Xenobiotic TargetsTargets

Glucoronidation Glucoronidation (most frequently (most frequently used by the used by the body)body)

Glucoronosyl-Glucoronosyl-

transferasestransferases

UDP-UDP-glucoronic glucoronic acidacid

2-acetylaminoflourene, benzoic 2-acetylaminoflourene, benzoic acid, aniline, phenolsacid, aniline, phenols

SulfationSulfation ------ PAPS PAPS (active (active sulfate)sulfate)

Alcohols, arylamines, phenolsAlcohols, arylamines, phenols

Conj. w/ Conj. w/ GlutathioneGlutathione

------ G-SH formG-SH form Electrophilic xenobiotics (R)Electrophilic xenobiotics (R)

R + G-SH R + G-SH R-S-G R-S-G

MethylationMethylation Methyl- Methyl- transferasestransferases

SAMSAM

AcetylationAcetylation Acetyl-CoAAcetyl-CoA isoniazidisoniazid