Date Published: April 1, 2012
Publisher: Hindawi Publishing Corporation
Author(s): Varsha G. Desai, Taewon Lee, Carrie L. Moland, William S. Branham, Roberta A. Mittelstaedt, Sherry M. Lewis, Julian E. A. Leakey, James C. Fuscoe.
The effects of 12-week exposure to zidovudine (AZT) at 400, 500, and 600 mg/kg/d were examined on expression of 542 mitochondria-related genes and mitochondrial DNA (mtDNA) copy number in the liver of male and female B6C3F1 mice to understand mitochondrial role in sex-related differences in development of lactic acidosis. Plasma lactate levels and hematologic parameters were also examined. Results indicated increased red blood cell (RBC) count in vehicle-treated controls, whereas a dose-related decline in the RBC count was noted in AZT-treated mice compared to the basal levels before treatments began. These decreases were associated with significant dose-related increases in mean corpuscular volume and mean corpuscular hemoglobin levels. This effect was greater in AZT-treated females compared to males. In both sexes, 12-week AZT or vehicle exposure significantly reduced plasma lactate levels compared to the basal levels. Results also showed modest, but significant, changes in the expression of genes associated with apoptosis and lipid metabolism at 600 mg/kg/d AZT. Neither drug nor sex influenced hepatic mtDNA copy number. Altogether, 12-week AZT exposure as high as 600 mg/kg/d did not impair hepatic mitochondria or induce lactic acidosis in B6C3F1 mice. However, AZT-mediated hematologic toxicity appeared to be greater in females compared to males.
The use of nucleoside reverse transcriptase inhibitors (NRTIs) in treatment of HIV-1 infections has been associated with a wide range of severe side effects, including lactic acidosis, hepatotoxicity, pancreatitis, lipodystrophy, neuropathy, and hematotoxicity . In addition, sex-related differences in the frequency and severity of NRTI-related adverse effects have been reported. It has been shown that women are less likely than men to tolerate NRTI therapy  and also are at higher risk for developing NRTI-related toxicities . Possible risk factors for sex-related differences in NRTI-induced toxicities include differences in body mass index, sex hormones, activities of kinases, drug-metabolizing enzymes, and the transport and excretion of the drug [4, 5]. Nonetheless, the molecular basis for an increased risk of developing NRTI-induced toxicity in HIV-1-infected women still remains unclear.
The present study evaluated liver mitochondria in AZT-treated B6C3F1 mice to understand the role of mitochondria in sex-related differences in the development of lactic acidosis. Both male and female B6C3F1 mice were treated with 400, 500, or 600 mg/kg/d AZT at doses predicted to severely alter mitochondrial function leading to hyperlactataemia/lactic acidosis. Despite the relatively high doses of AZT, there was no increase in plasma lactate levels in these mice. However, other classical parameters of clinical toxicity observed with AZT were altered and in a sex-related manner.