A patient on isoniazid develops peripheral neuropathy. The pharmacogenomic basis and the specific metabolic pathway involved are:
- A Slow N-acetyltransferase 2 (NAT2) phenotype causes isoniazid accumulation; excess isoniazid competes with pyridoxal-5'-phosphate (active B6) for pyridoxal kinase, reducing its availability for peripheral nerve metabolism ✓
- B Fast NAT2 phenotype causes rapid formation of toxic acetylhydrazine, directly damaging peripheral nerves
- C CYP2E1 polymorphism causes isoniazid accumulation independent of acetylation status
- D Isoniazid inhibits monoamine oxidase leading to neurotoxic serotonin accumulation
Correct answer: A. Slow N-acetyltransferase 2 (NAT2) phenotype causes isoniazid accumulation; excess isoniazid competes with pyridoxal-5'-phosphate (active B6) for pyridoxal kinase, reducing its availability for peripheral nerve metabolism
Explanation
Isoniazid is metabolized by NAT2 (N-acetyltransferase 2). Slow acetylators accumulate free isoniazid. Isoniazid forms hydrazones with pyridoxal (B6) and inhibits pyridoxal kinase, depleting pyridoxal-5'-phosphate (PLP). PLP is an essential cofactor for peripheral nerve amino acid metabolism (transaminations) and myelin synthesis. This B6-deficient peripheral neuropathy occurs predominantly in slow acetylators and is prevented by co-administration of pyridoxine (25–50 mg/day). Fast acetylators are at higher risk for hepatotoxicity via acetylhydrazine accumulation.
Reference: KD Tripathi, Essentials of Medical Pharmacology, 8th ed.
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