XENOBIOTIC METABOLISM IN ANIMALS

Swapanil Yadav
Head of Department
Department of Biotechnology
Gandhi Faiz -E- Aam College,
Shahjahanpur, U.P. 242001
swapanil@indiatimes.com

A compound foreign to a given organism is known as xenobiotic, e.g. Medicinal

drugs, agricultural chemicals, industrial chemicals and environmental contaminants. Drugs
such as antibiotics are not did not produce itself in human body nor are they part of normal
diet. Xenobiotics present a number of hazards to man and environment such as toxicity,
carcinogenicity and bioaccumulation. Many xenobiotics are recalcitrant and persist in the
environment. Xenobiotics are becoming a large increasingly problem in sewage treatment
system. Recalcitrant xenobiotic compounds are halocarbons (chloroform, DDT, BHC, lindane,
freons and dalapon etc.), polychlorinated biphenyles (PCB’s), synthetic polymers
(polyethylene, polystyrene and polyvinylchloride), alkyl benzyl sulphonates and oil mixtures.
Many hydrocarbons are cause of biomagnification. The disruption of the reproductive system
of male and female animals in the wild has been attributed to environmental chemicals, e.g.
DDT. Many compounds in the environment are capable of acting as endocrine disruptors, e.g.
chlordane, trans-nonachlor and PCB. Certain xenobiotics are very toxic even at low levels. On
the other hand, there are few xenobiotics, including drugs that do not exert some toxic effects if
sufficient amouts are administered. The toxic effects of xenobiotics cover a wide spectrum, but
the major effect can be considered under three general heading:
The first is cell injury which can be severe enough to result in cell death. Second,
the reactive species of a xenobiotic may bind to a protein, altering its antigenicity. Third,
reactions of activated species of chemical carcinogens with DNA are thought to be of great
importance in chemical carcinogenesis.
When xenobiotics enter in the body they take part in the metabolism, they become
deactivated by oxidation, reduction, hydrolysis, hydration and conjugation and finally secreted
by different routes such as urine, feces, breath and sweat. The enzymes that take part in
metabolism of xenobiotics are very important for the pharmaceutical industry. Liver plays
central role in modifying ingested substances because it is the only organ situated between the
intestine and systemic circulation.
William, R.T. in his book “Detoxification mechanism- The metabolism and detoxication of
drugs” described two phase metabolism of xenobiotic compounds. Phase I includes
oxidation, reductions and hydrolysis and phase II comprised of conjugation reactions.
According to him phase II reactions are actually detoxication reactions.

Hydroxylation
Hydroxylation is the chief reaction in phase I. Cytochrome P450 or monooxygenases is useful
to scientists of major fields such as molecular biology, pharmacology, biochemistry and
medicines. This class of oxygenases had requirements for both as oxidant (molecular oxygen)
and reductant (NADPH) which is called as ‘mixed function oxidases’. Human genome encodes
at least 14 families of these enzymes.
Oxidation and Reduction
Body has ability to oxidize cinnamic acid, benzene, toluene and o-xylene in hippuric acid,
phenol, benzoic acid and o-toluic acid. Body also has ability to reduce nitro groups to the
corresponding amines. 1939 Noble prize winner G. Domagk studied reduction of protonsil to
sulphanilamide, helpful in treptococcal infection treatment.
Acetylation and methylation
Acetyl–CoA is the acetyl donor in acetylation reactions. These reactions are catalyzed by
acetyltransferases present in cytosol of liver. The drug ioniazid, used in the treatment of
tuberculosis, is subjected to acetylation. A few xenobiotics are subject to methylation by
methyltransferases, employing S- adenosylmethionine as the methyl donor.
Sulfate conjugation
Oxidation product of benzene, phenol conjugates with sulfate to form phenyl sulfate. Baumann
was able to isolate and characterize phenol sulfate from the urine of a patient who had been
treated with phenol as an antiseptic. He also studied conjugation in catechol, bromobenzene,
indole and aniline. The sulfate donor in these and other biologic sulfation reactions is
adenosine 3’-phosphate-5’-phosphosulfate (PAPS).
Glucuronidation
First sugar conjugate euxanthic acid (Indian yellow) was isolated from the urine of cows fed
with mango leaves. Hydroxy-camphpor glucuronide was isolated after dose of camphor from
the urine of dogs. UDP-glucuronic acid is the glucuronyl donor, and a variety of
glucuronosyltransferases, present in both the endoplasmic reticulum and cytosol are catalyst.
Conjugation with glutathione
Glutathione is a tripeptide consisting of glutamic acid, cycteine, and glycine. A number of
xenobiotics conjugate with glutathione. The enzymes catalyzing these reactions are called
glutathione transferases and are present in higher amounts in liver cytosol.
Various factors affect the activities of the enzymes metabolizing xenobiotics. The activities of
these enzymes may differ substantially among species. There are significant differences in
enzyme activities among individuals, many of which appear to be due to genetic factors. The
activities of some of these enzymes vary according to age and sex. Intake of various
xenobiotics such as Phenobarbital, PCBs, or certain hydrocarbons can cause enzyme
induction.
Finally transporters recognize them and pumped out of cells which are excreted out
of animal body.