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Antimicrobial Agents and Chemotherapy, November 2003, p. 3384-3392, Vol. 47, No. 11
0066-4804/03/$08.00+0     DOI: 10.1128/AAC.47.11.3384-3392.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Mitochondrial and Metabolic Effects of Nucleoside Reverse Transcriptase Inhibitors (NRTIs) in Mice Receiving One of Five Single- and Three Dual-NRTI Treatments

INSERM Unité 481 and Centre Claude Bernard de Recherches sur les Hépatites Virales,¹ AP-HP, Service de Biochimie, Hôpital Beaujon, Clichy,⁴ Pharmacie, Hôpital Bichat,² INSERM Unité 393, Hôpital Necker-Enfants Malades,³ Unité de Pharmacovigilance, Hôpital Saint Antoine, Paris, France⁵

Received 7 November 2002/ Returned for modification 17 February 2003/ Accepted 15 July 2003

Although treatments with nucleoside reverse transcriptase inhibitors (NRTIs) can modify fat metabolism and fat distribution in humans, the mechanisms of these modifications and the roles of diverse NRTIs are unknown. We studied the mitochondrial and metabolic effects of stavudine (d4T), zidovudine (AZT), didanosine (ddI), lamivudine (3TC), zalcitabine (ddC), and three combinations (AZT-3TC, d4T-3TC, and d4T-ddI) in mice treated for 2 weeks with daily doses equivalent to the human dose per body area. Concentrations of AZT and d4T in plasma were lower when these drugs were administered with 3TC or ddI. Whatever the treatment, mitochondrial DNA was not significantly decreased in muscle, heart, brain, or white adipose tissue but was moderately decreased in liver tissue after the administration of AZT, 3TC, or d4T alone. Blood lactate was unchanged, even when NRTIs were administered at supratherapeutic doses. In contrast, the level of plasma ketone bodies increased with the administration of AZT or high doses of d4T but not with ddC, 3TC, or ddI, suggesting that the thymine moiety could be involved. Indeed, the levels of plasma ketone bodies increased in mice treated with ß-aminoisobutyric acid, a thymine catabolite. Treatment with AZT, d4T, or ß-aminoisobutyric acid increased hepatic carnitine palmitoyltransferase I (CPT-I) mRNA expression and the mitochondrial generation of ketone bodies from palmitate. In conclusion, therapeutic doses of NRTIs have no or moderate effects on mitochondrial DNA and no effects on plasma lactate in mice. However, AZT and high doses of d4T increase the levels of hepatic CPT-I, mitochondrial fatty acid ß-oxidation, and ketone bodies, and these catabolic effects are reproduced by ß-aminoisobutyric acid, a thymine metabolite.