The prevention of mother-to-child transmission (MTCT) of HIV is a crucial component in HIV therapy. Nucleoside reverse transcriptase inhibitors (NRTIs), primarily 3=-azido-3=-thymidine (AZT [zidovudine]), have been used to treat both mothers and neonates. While AZT is being replaced with less toxic drugs in treating mothers in MTCT prevention, it is still commonly used to treat neonates. Problems related to mitochondrial toxicity and potential mutagenesis associated with AZT treatment have been reported in treated cohorts. Yet little is known concerning the metabolism and potential toxicity of AZT on embryonic and neonatal tissues, especially considering that the enzymes of nucleoside metabolism change dramatically as many tissues convert from hyperplastic to hypertrophic growth during this period. AZT is known to inhibit thymidine phosphorylation and potentially alter deoxynucleoside triphosphate (dNTP) pools in adults. This study examines the effects of AZT on dNTP pools, mRNA expression of deoxynucleoside/deoxynucleotide metabolic enzymes, and mitochondrial DNA levels in a neonatal rat model. Results show that AZT treatment dramatically altered dNTP pools in the first 7 days of life after birth, which normalized to agematched controls in the second and third weeks. Additionally, AZT treatment dramatically increased the mRNA levels of many enzymes involved in deoxynucleotide synthesis and mitochondrial biogenesis during the first week of life, which normalized to age-matched controls by the third week. These results were correlated with depletion of mitochondrial DNA noted in the second week. Taken together, results demonstrated that AZT treatment has a powerful effect on the deoxynucleotide synthesis pathways that may be associated with toxicity and mutagenesis. N ucleoside reverse transcriptase inhibitors (NRTIs) are an important class of drug used primarily in treatment of the HIV infection and prevention of mother-to-child transmission (MTCT) of the virus. One of these NRTIs, 3=-azido-3=-thymidine (AZT [zidovudine]), is of interest as it is commonly used as a component of treatment for pregnant mothers and their newborn children. AZT was developed in 1974 as a cancer treatment drug, but in 1984 it was found to be more effective in treating HIV. Since then, it has been a major drug of choice used in highly active antiretroviral therapy (HAART) worldwide in adults, mothers, and their infants (1-3). While it is now being replaced with less toxic drugs, it is still commonly used to treat neonates (4, 5), in which AZT is highly efficient in preventing HIV transmission. AZT is given as a prodrug that must be phosphorylated by the host cell to AZT-triphosphate (AZT-TP), an analogue of TTP, in order to inhibit viral replication. While its metabolism and toxicity in adults have been well characterized, fetal and neonatal metabolism and toxicity have not been studied. Clinical manifestations, including suppression of bone marrow and anemia with low hemoglobin levels, have been reported in AIDS patients treated with ...

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