Like other antihuman immunodeficiency virus
dideoxynucleosides,
stavudine may occasionally induce
lactic acidosis and perhaps
lipodystrophy in metabolically or genetically susceptible patients. We studied the effects of
stavudine on
mitochondrial DNA (
mtDNA),
fatty acid oxidation, and blood metabolites in lean and genetically obese (ob/ob) mice. In lean mice,
mtDNA was depleted in liver and skeletal muscle, but not heart and brain, after 6 weeks of
stavudine treatment (500 mg/kg/day). With 100 mg/kg/day,
mtDNA transiently decreased in liver, but was unchanged at 6 weeks in all organs, including white adipose tissue (WAT). Despite unchanged
mtDNA levels, lack of significant oxidative
mtDNA lesions (as assessed by long polymerase chain reaction experiments), and normal blood
lactate/
pyruvate ratios, lean mice treated with
stavudine for 6 weeks had increased fasting blood
ketone bodies, due to both increased hepatic
fatty acid beta-oxidation and decreased peripheral ketolysis. In obese mice, basal WAT
mtDNA was low and was further decreased by
stavudine. In conclusion,
stavudine can decrease hepatic and muscle
mtDNA in lean mice and can also cause
ketoacidosis during fasting without altering
mtDNA.
Stavudine depletes WAT
mtDNA only in obese mice. Fasting and
ketoacidosis could trigger decompensation in patients with incipient
lactic acidosis, whereas WAT
mtDNA depletion could cause
lipodystrophy in genetically susceptible patients.