Transcript examples of carcinogenic xenobiotics

The Metabolism of
XENOBIOTICS
Reported by Group III, 1-C2
What are Xenobiotics?
•Amay
be naturalthat
or synthetic
foreign to the body.
compound
is “stranger”
• may be harmful or safe
EXAMPLES OF CARCINOGENIC XENOBIOTICS
• Food components methyl glyoxal (coffee)
Xenoaflatoxin
• Food contaminants
B1
=
• Cigarette smoke
• Industrial (occupational)dibromoethane
• Industrial (effluent) vinyl chloride
•Cyanide is one example which is toxic at very
low levels
Principal Classes of Xenobiotics
Drugs
Chemical carcinogens
PCB’s
Insecticides
Most synthetic materials
There are 200,000 of these
How does the body handle them?
For convenience, the metabolism of
xenobiotics is divided into 2 phases
There are approximately 30 different
enzymes that catalyze xenobiotic
compounds
1. Phase 1
•Most common reaction: hydroxylation
2 phases
•Some enzymes: monooxygenases
microsomal cytochrome-P450s
2. Phase 2
•Most common reactions: conjugation
methylation
•Enzymes: transferases
Phase 1
Mainly hydroxylation reactions
Enzyme: Microsomal Cytochromes P450s
Purpose:
1. Make the toxin more water-soluble
2. Sometimes deactivates the toxin
Phase 1:
Microsomal cytochrome P450s
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Large number of isoforms
All contains heme
Has a special nomenclature:
CYP
Family
2
CYPs with
>40%
similarity
Subfamily
C
CYPs with
>55%
similarity
Specific
9 #
CYPs with
>100% (exact)
similarity
Phase 1:
= A cytochrome that metabolizes
warfarin
CYP
2
C
9
Phase 1:
Microsomal cytochrome P450s
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Large number of isoforms
All contains heme
Has a special nomenclature:
Plenty in liver (in the SER)
Differs from the mitochondrial cytochrome P450
Has lipid components (primarily lecithin)
Inducible (CYP2C9)
Some exhibit polymorphism
Rarely, some contribute to cancer formation
Phase 1:
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Inducible (CYP2C9)
Microsomal cytochrome P450s
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Large number of isoforms
All contains heme
Has a special nomenclature:
Plenty in liver (in the SER)
Differs from the mitochondrial cytochrome P450
Has lipid components (primarily lecithin)
Inducible (CYP2C9)
Some exhibit polymorphism
Rarely, some contribute to cancer formation
Phase 1:

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:
Microsomal cytochrome P450s
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Large number of isoforms
All contains heme
Has a special nomenclature:
Plenty in liver (in the SER)
Differs from the mitochondrial cytochrome P450
Has lipid components (primarily lecithin)
Inducible (CYP2C9)
Some exhibit polymorphism
Rarely, some contribute to cancer formation
Phase 1:
CYP1A1, CYP2E1:
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.
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Rarely, some contribute to cancer formation
Phase 1:
Microsomal cytochrome P450s
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Large number of isoforms
All contains heme
Has a special nomenclature:
Plenty in liver (in the SER)
Differs from the mitochondrial cytochrome P450
Has lipid components (primarily lecithin)
Inducible (CYP2C9)
Some exhibit polymorphism
Rarely, some contribute to cancer formation
Phase 1:
CYP2D6
CYP2D6 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.
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The poor catalysis of debrisoquin and sparteine allows them
to stay and accumulate in the body and cause toxicity.
Some exhibit polymorphism
Polymorphisms and differences between enzyme structure
between individuals is genetic
Phase 2
Conjugation reactions
Enzyme: Transferases
Purpose: Make the toxin further watersoluble for excretion
Xenobiotic
Processing of Xenobiotics
Out
Reactive Metabolite
Nontoxic Metabolite
Cell injury
Hapten
Mutation
Antibody
reaction
Cancer
Phase 2:
Conjugation
Rxn
Glucoronidation
(most frequently
used by the
body)
Enzyme
Glucoronosyltransferases
Donor
Examples of Xenobiotic
Targets
UDPglucoronic
acid
2-acetylaminoflourene, benzoic
acid, aniline, phenols
Sulfation
---
PAPS
(active
sulfate)
Alcohols, arylamines, phenols
Conj. w/
Glutathione
---
G-SH form
Electrophilic xenobiotics (R)
R + G-SH  R-S-G
Methylation
Acetylation
Methyltransferases
SAM
Acetyl-CoA isoniazid