A patient on long-term isoniazid therapy develops peripheral neuropathy with sensory loss, burning paresthesias, and elevated serum homocysteine. Which biochemical mechanism explains the neuropathy?

• A Isoniazid inhibits pantothenate kinase, blocking CoA synthesis and axonal energy metabolism
• B Isoniazid forms a hydrazone with pyridoxal phosphate (PLP), depleting the active B6 coenzyme required for transamination and amino acid metabolism including myelin maintenance ✓
• C Isoniazid causes folate deficiency by inhibiting dihydrofolate reductase
• D Isoniazid oxidizes cobalamin, preventing methylmalonyl-CoA mutase function

Explanation

Isoniazid (INH) acts as a hydrazide and condenses covalently with pyridoxal (aldehyde form of B6) to form an inactive hydrazone complex, dramatically reducing PLP levels. PLP is required as cofactor for >100 enzymes including transaminases, cystathionine beta-synthase, and amino acid decarboxylases. PLP depletion impairs myelin sphingolipid synthesis and amino acid metabolism, causing peripheral neuropathy. Elevated homocysteine results from impaired CBS (PLP-dependent). Prophylactic pyridoxine (25-50 mg/day) is co-prescribed with INH to prevent this complication.

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

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