Abstract
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 β-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.
Footnotes
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Send reprint requests to: Dr. Bernard Fromenty, INSERM U-481, Hôpital Beaujon, 100 Bd du Général Leclerc, 92118 Clichy Cedex, France. E-mail:fromenty{at}bichat.inserm.fr
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This work was supported in part by the University of Paris 7-Denis Diderot (Convention A007 relatif à l'appel d'offre SIDA), the Program Hospitalier de Recherche Clinique 95-96, and the Réseau Hepatox. M.M. was a recipient of a fellowship from the Fondation pour la Recherche Médicale.
- Abbreviations:
- HIV
- human immunodeficiency virus
- mtDNA
- mitochondrial DNA
- WAT
- white adipose tissue
- nDNA
- nuclear DNA
- PCR
- polymerase chain reaction
- AP
- apurinic/apyrimidinic
- bp
- base pair
- TBAR
- thiobarbituric acid reactant
- Received August 25, 2000.
- Accepted January 14, 2001.
- The American Society for Pharmacology and Experimental Therapeutics
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