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Xenobiotics - Biochemistry Short Note

Xenobiotics are chemical substances foreign to the human body. They have no normal physiological role and may be harmful in excess.
Examples: drugs, food additives, pesticides, insecticides, cosmetics, pollutants, polycyclic hydrocarbons, and chemical carcinogens.
Basic Medical Biochemistry - A Clinical Approach, 6e, p. 15

Why are xenobiotics metabolized?

Most are lipid-soluble. If not converted to water-soluble products, they may accumulate in the body. Their metabolism, chiefly in the liver, makes them suitable for elimination through urine or bile.
Metabolism usually detoxifies compounds, but can sometimes produce:
  • An active drug from a prodrug
  • A toxic metabolite
  • A mutagen or carcinogen from an initially harmless compound

Phases of xenobiotic metabolism

Phase I - Functionalization reactions

Phase I introduces or exposes a functional group such as -OH, -NH₂, -SH, or -COOH, making the compound more reactive and usually somewhat more polar.
Main reactions
  1. Oxidation
  2. Reduction
  3. Hydrolysis
Most important reaction: hydroxylation by the cytochrome P450 monooxygenase system.
Location: Smooth endoplasmic reticulum of hepatocytes, called the microsomal drug-metabolizing system. CYP enzymes are also present in intestinal cells.

Cytochrome P450 reaction

[ RH + O_2 + NADPH + H^+ \rightarrow ROH + H_2O + NADP^+ ]
Where:
  • RH = xenobiotic substrate
  • ROH = hydroxylated product
  • NADPH-cytochrome P450 reductase transfers electrons from NADPH to CYP450.
One oxygen atom is incorporated into the substrate; the other is reduced to water.
Harper's Illustrated Biochemistry, 32nd ed, p. 576
Phase I reactions include
  • Hydroxylation
  • Dealkylation
  • Deamination
  • Dehalogenation
  • Desulfuration
  • Epoxidation
  • Reduction
  • Ester hydrolysis by esterases

Important CYP families

The main CYP families involved in drug metabolism are:
  • CYP1
  • CYP2
  • CYP3
Clinically important examples include CYP3A4, CYP2D6, CYP2C9, CYP2C19, CYP1A2, and CYP2E1.

Phase II - Conjugation reactions

In Phase II, the parent xenobiotic or its Phase I metabolite combines with a water-soluble endogenous compound. This produces a highly polar product that can be excreted in urine or bile.

Major conjugation reactions

ReactionDonor / cofactorEnzyme
GlucuronidationUDP-glucuronic acidUDP-glucuronosyl transferase
SulfationPAPSSulfotransferase
Glutathione conjugationReduced glutathione, GSHGlutathione S-transferase
AcetylationAcetyl-CoAN-acetyltransferase
MethylationS-adenosylmethionine, SAMMethyltransferase
Amino acid conjugationGlycine or other amino acidsSpecific transferases

1. Glucuronidation

  • Most frequent conjugation reaction.
  • Uses UDP-glucuronic acid.
  • Drugs, bilirubin, steroid hormones, phenols, benzoic acid, and some carcinogens can form glucuronides.
  • The glucuronide may attach to oxygen, nitrogen, or sulfur atoms.
    Harper's Illustrated Biochemistry, 32nd ed, p. 577

2. Sulfation

  • Important for alcohols, phenols, and arylamines.
  • Sulfate donor is PAPS: 3'-phosphoadenosine-5'-phosphosulfate.

3. Glutathione conjugation

  • Detoxifies reactive electrophilic metabolites.
  • Catalyzed by glutathione S-transferase (GST).
  • Ultimately produces mercapturic acids, excreted in urine.
[ R + GSH \rightarrow R-S-G ]
Glutathione depletion permits reactive metabolites to bind cellular proteins and cause injury. This is central to paracetamol poisoning.
Harper's Illustrated Biochemistry, 32nd ed, pp. 577-578

4. Acetylation

  • Acetyl donor: acetyl-CoA.
  • Important drugs: isoniazid, sulfonamides, hydralazine.
  • Shows genetic variation: individuals may be slow or fast acetylators.

5. Methylation

  • Methyl donor: SAM.
  • Unlike most conjugations, methylation may not increase water solubility substantially.

Enzyme induction and inhibition

Enzyme induction

Certain drugs increase CYP enzyme synthesis, increasing metabolism of substrates.
Examples of inducers
  • Rifampicin
  • Phenobarbital
  • Phenytoin
  • Carbamazepine
  • Chronic alcohol use induces CYP2E1
Effects
  • Faster metabolism of drugs
  • Reduced drug concentration and therapeutic effect
  • May increase formation of toxic metabolites

Enzyme inhibition

Some drugs inhibit CYP enzymes and reduce metabolism of other drugs.
Examples
  • Cimetidine
  • Erythromycin/clarithromycin
  • Azole antifungals
  • Grapefruit juice
  • Chloramphenicol
Effects
  • Increased plasma drug level
  • Increased duration of action
  • Risk of toxicity

Important clinical examples

Paracetamol toxicity

  • Most paracetamol is normally conjugated with glucuronide and sulfate.
  • A small fraction is oxidized by CYP2E1 to a toxic metabolite, NAPQI.
  • NAPQI is normally detoxified by GSH.
  • In overdose, GSH is depleted, allowing NAPQI to cause hepatic necrosis.
  • N-acetylcysteine replenishes glutathione and is the antidote.

Benzo[a]pyrene

A polycyclic hydrocarbon in cigarette smoke and charred foods may be converted by CYP450 to reactive epoxide metabolites that can damage DNA and promote cancer.

One-line exam summary

Xenobiotics are foreign, usually lipid-soluble chemicals metabolized mainly in the liver through Phase I functionalization reactions, chiefly CYP450 oxidation, followed by Phase II conjugation reactions, producing water-soluble metabolites excreted in urine or bile.
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