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

Abstract

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 ␤-aminoisobutyric acid, a thymine catabolite. Treatment with AZT, d4T, or ␤-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 ␤-oxidation, and ketone bodies, and these catabolic effects are reproduced by ␤-aminoisobutyric acid, a thymine metabolite.

A brief overview of mechanisms of mitochondrial toxicity from NRTIs

“…Transgenic mouse studies demonstrate that the expression of HIV gene product Tat sensitizes tissues and alters antioxidant defenses and suppression of mitochondrial superoxide dismutase activity [Flores et al, 1993]. NRTI-induced oxidative stress occurs in lymphoid [Yamaguchi et al, 2002] and nonlymphoid tissues and in skeletal muscle in mice [de la Asuncion et al, 1998;Note et al, 2003] and rats [Szabados et al, 1999;Collins et al, 2004] treated with AZT.…”

Mitochondrial DNA Depletion in Rat Liver Induced by Fosalvudine Tidoxil, a Novel Nucleoside Reverse Transcriptase Inhibitor Prodrug

“…With respect to body surface area, the 15-mg/kg dose of fosalvudine in rats is about 3.8-fold higher than the highest dose administered to humans (40 mg/m 2 ) (3, 16). As a positive control, a fourth group of rats received 100 mg/kg/day of didanosine (Changzhou Huaren Chemical Co., Jiangsu, China), a higher dose than the 66 mg/kg/day which was shown previously to induce mitochondrial hepatotoxicity in mice (13). As a negative control, a fifth group of rats was treated with water on the same schedule as the drug treatment.…”

Noise-induced hearing loss in mice treated with antiretroviral drugs

“…However, it was noted that the experimental mice were visibly thinner than the control mice, but this weight loss did not seem to be due to a lack of water consumption. In mouse studies, these drugs are frequently given orally, usually by gavage, but they can also be given in the drinking water (e.g., Ayers et al 1997;Note et al 2003). We chose the drinking-water approach, because of the ease of administration over the long 3-mo time frame.…”