Zidovudine (ZDV), the mainstay of antiretroviral therapy for HIV-1 infection, has associated toxicities which may be dose limiting and may reduce long term tolerance of this medication. Skeletal myopathy, cardiomyopathy, and hepatic dysfunction related to ZDV have been associated with structural changes in mitochondria. To evaluate low dose effects ZDV, 0.2 mg/ml, was added to the water supply of pregnant Sprague-Dawley rats and their infant rats. At 28 days of life the ZDV dose was increased in half the infant rats to 1.0 mg/ml. Control rats received water without ZDV and therapy was continued for 60 days. At various time points heart, liver and brain tissue fatty acid oxidation, lipid peroxides, antioxidant enzyme activity (catalase - CAT, superoxide dismutase - SOD, and glutathione peroxidase - GPx) and microscopic structure were analyzed. Oxidation of medium chain (MCFA, C6-C12), long chain(LCFA, C14-C20), very long chain (VLCFA, >22) and branched chain (phytanic acid, PA) fatty acids, were measured in tissue homogenates.

CAT or GPx activity were not effected but SOD was reduced in heart at 60 days and lipid peroxides were increased. Fatty acid oxidation was significantly altered with both ZDV dose regimens. No significant changes were observed for VLCFA or PA oxidation, but MCFA and LCFA oxidation, a mitochondrial function, were reduced compared to controls. Heart tissue demonstrated the greatest reduction of MCFA oxidation at both doses and related to duration of exposure (45% of control, 60 days, 1 mg/ml). Brain and liver demonstrated less reduction of MCFA oxidation. LCFA oxidation was reduced in heart tissue at both low and high doses at 60 days and for liver and brain at high dose. Although decreased LCFA and MCFA oxidation suggest mitochondrial effect, no structural changes were visualized on light or electron microscopy. These results suggest the possibility that accumulation of MCFA and LCFA may account at least in part for observed ZDV toxicity and provide a mechanistic rationale for potential efficacy of therapies such as carnitine in reducing ZDV toxicity.