Mitochondrial toxicity of AZT-3TC in experimental models

Lovelace Biomedical &Environmental Res, Albuquerque NM

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Abstract

DESCRIPTION (provided by applicant): Nucleoside reverse transcriptase inhibitors (NRTIs) when given in combination are highly effective in reducing the vertical transmission of HIV-1 from mother to infant; however, these drugs may impose a risk for cancer and mitochondria! disease later in life in exposed children. The objective of this study is to determine the relative impact of AZT, 3TC, and AZT-3TC on mitochondrial structure and function in human lymphoblastoid cells exposed in vitro and in lymphocytes and hearts of mice exposed transplacentally. The long-term objective is to determine whether NRTI-induced mtDNA mutations play a critical role in temporal changes in mitochondrial structure and function in heart and other tissues/cell types. Two specific aims will be accomplished: 1. to determine the relative ability of AZT-3TC to induce toxicity by defining genotoxicity, mutagenicity and altered mitochondrial structure and function 2. To compare, at birth and 3 months of age, mitochondrial toxicity in cardiac tissue and lymphocytes following transplacental exposure of female B6C3F1 mice to AZT, 3TC or AZT-3TC.