Metabolism of Xenobiotics
20 (Detoxification)
1. Define xenobiotic.
Xenobiotic is a compound that is foreign to the body. It may include drugs, chemical
carcinogens, polychlorinated biphenyls (PCBs) and insecticides.
2. Explain the process of detoxification with examples.
Detoxification: It is a process by which toxic compounds are converted into less toxic
and easily excretable forms.
Sites of Xenobiotic Metabolism
i. Liver: It is a major site for detoxification.
ii. Non-hepatic sites: Intestinal mucosa, kidney, lung, gastrointestinal (GI) tract and placenta.
Xenobiotics are Detoxified in Two Phases
Phase 1
Attachment of new functional groups or transformation of existing functional groups by hy-
drolysis, oxidation, reduction, etc.
i. Oxidation: It is the removal of hydrogen or addition of oxygen. Oxidation is carried out by
CYP450 system, alcohol dehydrogenase, aldehyde dehydrogenase and monoamine oxidase.
For example,
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ii. Reduction: It is the removal of oxygen and addition of hydrogen or electrons.
For example,
iii. Hydrolysis: It is the breakdown of compounds by addition of water.
For example,
Metabolism of Xenobiotics (Detoxification)
Phase 2
Conjugation: The existing functional group of a compound is conjugated by glucuronidation,
acetylation, methylation, attachment of an amino acid or other mechanisms. Most of the con-
jugated compounds are water soluble and can be easily excreted.
i. Glucuronidation: The compound is conjugated with glucuronic acid.
For example,
ii. Conjugation with glycine.
For example,
iii. Acetylation.
For example,
iv. Methylation.
For example,
v. Sulfation.
For example,
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262 Quick Review of Biochemistry for Undergraduates
3. How are the following compounds detoxified?
i. Indole.
ii. Aspirin.
iii. Paracetamol.
iv. Cyanide.
v. Phenobarbital.
Metabolism of Xenobiotics (Detoxification)
vi. Isoniazid.
i. Indole: Undergoes deamination and decarboxylation to produce indolepyruvate and finally
indoleacetate.
ii. Aspirin: It is detoxified by hydrolysis.
iii. Paracetamol (acetaminophen): It is detoxified by both glucuronidation and sulfation.
Paracetamol can also be detoxified by CYP2E1 to produce N-acetyl-p-benzoquinoneimine
(NAPQI), which conjugates with glutathione (GSH) to form inactive compound.
iv. Cyanide: Conjugates with thiosulfate to form less toxic thiocyanate.
v. Phenobarbital: Detoxified by hydroxylation by CYP450 group of monooxygenases in the
liver followed by glucuronidation.
vi. Isoniazid (antitubercular drug): Undergoes acetylation. Genetic variations in the enzymes
(acetyl transferases) lead to slow and fast acetylators.
4. Explain the role of glutathione in detoxification mechanism.
i. Glutathione (γ-glutamyl-cysteinylglycine) is a tripeptide consisting of glutamic acid, cysteine
and glycine.
ii. Carcinogens (R) are conjugated with GSH, a reaction catalyzed by glutathione S-transferase
to form glutathione conjugate, which is further metabolized and excreted as mercapturic
acid (Fig. 20.1).
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Metabolism of Xenobiotics (Detoxification)
Fig. 20.1: Detoxification by glutathione
Key Points
N-acetyl-p-benzoquinoneimine (NAPQI): It is a metabolite (minor) of paracetamol. It is detoxified by
conjugation with glutathione. In paracetamol overdose, excess NAPQI is generated, which depletes
the hepatic glutathione stores and then causes damage to liver.
Most isoforms of CYP450 are induced by certain drugs: For example, administration of phe-
nobarbital causes hypertrophy of smooth ER 3–4 folds in 4–5 days. This can result in increased
metabolism of drugs.
Warfarin: Used to prevent blood clotting, is metabolized by CYP2C9, which is induced by
phenob arbital. Thus, when warfarin is coadministered with phenobarbital, warfarin is rapidly
metabolized.
Ethanol induces CYP2E1: Which increases the risk for carcinogenicity in alcoholics.
Certain isoforms of CYP450 (CYP1A1): Are involved in the metabolism of polycyclic aromatic
hydrocarbons (PAHs) and are also responsible for carcinogenesis produced by these agents. For
example, in the lung, it is involved in the conversion of inactive PAH inhaled by smoking to active
carcinogens by hydroxylation.
Certain CYP450 enzymes exhibit genetic polymorphism: Some of them show low catalytic activ-
ity. This explains variations in drug responses noted among patients.
Activity of CYP450 is also affected by tissue or organ disease (e.g. cirrhosis of liver).
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