Metabolism of Xenobiotics

Wiryatun Lestariana
Biochemistry Department
Fac. of Medicine
Gadjah Mada University

Xenobiotic Metabolism
Introduction
Metabolism of xenobiotics before being
excreted
Isoforms of cytochrome P450
Conjugation reactions
The activities of xenobiotic-metabolizing
enzymes
Responses to xenobiotics

Introduction
Xenobiotic: is compound that foreign to
the body (drugs, food additives, pollutants,
incecticides, etc.)
Metabolism of xenobiotics are basic to a
rational understanding of
- pharmacology
- therapeutics
- pharmacy
- toxicology
- management of cancer
- drug addiction

continued
Xenobiotics that must be metabolized
before being excreted with the liver being
the main organ involved
A xenobiotic may be excreted unchanged
The term detoxification is sometimes
used for many of the reactions involved in
metabolism of xenobiotics

Metabolism of xenobiotics
Divided in 2 phases
Phase 1: hydroxilation, catalyzed by
members of a class of enzymes:
monooxygenases or cytochrome P450s
Phase 2: the hydroxylated or other compounds
produced in phase 1 by specific
enzymes, converted to
various
polar metabolites by conjugation with
glucuronic acid, sulfate, acetate,
glutathion, or certain amino acids,
or by methylation

Isoforms of cytochrome P450s

The human genome encodes at least 14 families
The reaction catalyzed by cytochrome P450
RH + O2 + NADPH + H+

R-OH +H2O + NADP

In this reaction use 1atom of oxygen only for forming ROH

monooxygenases
mixed function oxidases and
the reaction can be represented :
reduced cytochrome P450

oxidized cytochrome P450

RH + O2

ROH + H2O

RH
represent of xenobiotics
( drugs, carcinogens, pesticides, petroleum
products, and pollutants
Endogenous compounds (certain steroids,
eicosanoids, fatty acids, retinoids are also
substrates for cytochrome P450
The substrates are generally lipophilic by
hydroxylation
hydrophilic

continued

Conjugation reactions
1. glukuronidation
- the substrates such as aniline, benzoic acid, phenol,
and many steroids are excreted as glukuronides
the glucuronidation may be attached to
oxygen, nitrogen, or sulfur of the substrates
the most frequent conjugation reaction
2. sulfation
- the substrate such as alcohol, arylamines,
and phenol are sulfated
- the sulfate donor: adenosine 3-phophate-5-phospho
sulphate (PAPS)
active sulfate

continued

3. conjugation with glutathione

- glutation (-glutamyl-cysteinylglycine
(tripeptide consisting of glutamic acid,
cysteine and glycine)
- gluthatione is abbreviated
GSH
- -SH (sulfhidryl group of its cysteine)
8,9-aflatoxine epoxide + GSH
toxic

GSH conjugate
not toxic

- if the potentially toxic xenobiotics were not

conjugated to GSH
they would be free to
combine covalently with DNA, RNA, or cell
protein
lead to serious cell damage

Glutathione
Has important functions in human cells apart
from its role in xenobiotic metabolism
- participates in the decomposition of
potentially toxic H2O2 in catalyzed by
glutathione peroxidase
- an important intracellular reductant
to maintain essential SH groups of
enzyme in their reduced state

continued
- metabolic cycle involving GSH as carrier has been
in the transport of certain amino acids across
membrane in the kidney
amino acid + GSH
-glutamyl amino acid
+ cysteinylglycine
Other reactions
- acetylation
- methylation

Acetylation
acetyltransferase (cytosol)

* X + Acetyl-CoA
Acetyyl-X + CoA
* X
= xenobiotcs (eg, isoniazid)
* acetyl-CoA = active acetate
acetyl
donor
* Exist of polymorphic of acetyltransferase
resulting individuals is classified
slow or fast acelators
rate of
clearance of drug

Continued

- slow acelators (eg, isoniazid)

toxic
effect of isoniazid because the drug
persist longer in these individuals
* Methylation
- a few xenobiotics are subjects to
methylation by methyltransferase
- S-adenosylmethionin = methyl donor

Factors which affecting the activity

of xenobiotic-metabolism enzymes
- may differ substantially among species
the possible toxicity or
carcinogenicity of xenobiotic cannot be
extrapolated freely from one species to
another
- are significant differences in enzyme
activities among individuals

continued
- many of which appear to be to genetic factors
- some of these enzyme vary according to age
and sex
- some of xenobiotics can cause enzyme
induction
- metabolites of certain xenobiotics
can
inhibit or stimulate the activities enzyme
this can affect the doses of certain drugs that
are administrated to pasients

 Responses to xenobiotics include

- pharmacologic
- toxic
- carcinogenic effecs
Pharmacologic
- when the xenobiotic is a drug
phase 1
reaction may produce
- its active form or
- diminish its action or
- terminate its action if the drug
is pharmacologically active in the body without
prior metabolism

continued

Toxic
- certain xenobiotics are very toxic even at low
levels (eg:cyanide)
- the toxic effectof xenobiotics cover a wide
spectrum
three general healdings
1. cell injury (cytotoxicity)
cell death
2. reactive species of xenobiotic may bind to a
protein
altering its antigenicity
act as a hapten
damage the cell
3. reactions of activated species of chemical
carcinogens with DNA
to be of great
importance in chemical carcinogenesis

GSH S- transferase or
Cytochrome P450

Xenobiotic

epoxide hydrolase

Reactive metabolite

Nontoxic metabolic

Covalent binding to
macromolecules
Cell enjury

Hapten
Antibody production

Mutation
Cancer

Cell injury
Figure: Metabolism of Xenobiotic can result in cell injury,
lmmunologic damage, or cancer

Alcoholism
Alcoholism
leads to fat accumulation in
liver
hiperlipidemia
cirrhosis
Ethanol consumption over a long period
oxidation by alcohol dehydrogenase
leads to exess production of NADH
Alcohol dehydrogenase

CH3-CH2-OH

ethanol

CH 3-CHO
NAD+ NADH + H+

acetaldehyde
reactive metabolite

cell injury

mutation

cancer