Phase II drug metabolism (conjugation reactions) generally increases water solubility for renal excretion. Which phase II reaction is responsible for the metabolism of isoniazid (INH) and is genetically polymorphic, affecting drug toxicity?
- A Glucuronidation — catalyzed by UGT1A enzymes
- B Sulfation — catalyzed by SULT1A1
- C N-acetylation — catalyzed by N-acetyltransferase 2 (NAT2) ✓
- D Methylation — catalyzed by COMT
Explanation
Isoniazid is metabolized primarily by N-acetylation catalyzed by hepatic N-acetyltransferase 2 (NAT2), which converts INH to acetyl-INH. NAT2 is genetically polymorphic: slow acetylators (autosomal recessive; ~50% of Europeans and Africans) have lower NAT2 activity and accumulate higher INH levels, resulting in increased risk of peripheral neuropathy (prevented by pyridoxine) and drug interactions. Rapid acetylators eliminate INH faster, reducing efficacy; rapid acetylators may also produce more hydrazine (a toxic metabolite), potentially increasing hepatotoxicity risk. NAT2 acetylator status is also relevant for dapsone, procainamide, hydralazine, and sulphamethazine.
Reference: Harper's Illustrated Biochemistry, 32nd ed.
High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP
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