CYP1A1 is strongly induced by polycyclic aromatic hydrocarbons (PAH) from cigarette smoke via the aryl hydrocarbon receptor (AhR). What is the toxicological consequence of CYP1A1 induction?

• A Rapid detoxification of PAH to water-soluble excretable forms
• B Bioactivation of PAH to reactive epoxides (diol-epoxides) that form DNA adducts ✓
• C Induction of Phase II conjugation enzymes reducing PAH toxicity
• D Conversion of PAH to reactive oxygen species only, without forming DNA adducts

Explanation

CYP1A1-induced oxidative metabolism of PAH (e.g., benzo[a]pyrene) produces epoxide intermediates (arene oxides) that are further metabolized to diol-epoxides — highly electrophilic compounds that form stable covalent adducts with guanine residues in DNA. These DNA adducts, if not repaired, cause G→T transversions in critical genes (notably TP53, KRAS), initiating carcinogenesis. This is a paradigmatic example of metabolic bioactivation (a toxicological paradox: CYP enzymes designed for detoxification can bioactivate carcinogens). Phase II enzymes (option C) are separately induced but are downstream of, and do not prevent, the CYP1A1-mediated bioactivation step.

Reference: Harper's Illustrated Biochemistry, 32nd ed.

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