A 34-year-old man with HIV on antiretroviral therapy including stavudine presents with progressive painful sensory neuropathy in a glove-and-stocking distribution and elevated serum lactate. Stavudine causes this mitochondrial toxicity by inhibiting which enzyme?

• A Mitochondrial DNA polymerase gamma ✓
• B HIV reverse transcriptase
• C Dihydroorotate dehydrogenase
• D Ribonucleotide reductase

Explanation

Stavudine and other dideoxynucleoside analogs (didanosine, zalcitabine) inhibit mitochondrial DNA polymerase gamma, depleting mitochondrial DNA and causing lactic acidosis, peripheral neuropathy, and lipodystrophy. HIV reverse transcriptase is their therapeutic target but does not explain the toxicity. Dihydroorotate dehydrogenase is inhibited by leflunomide. Ribonucleotide reductase is inhibited by hydroxyurea.

Reference: Katzung's Basic and Clinical Pharmacology, 15th ed.

High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP

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