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Revista de SIDA e investigación clínica

Oxidative Damage is not a Major Contributor to AZT-Induced Mitochondrial Mutations

Abstract

Adam E Osborne, J Aquiles Sanchez, Lawrence J Wangh, Ravigadevi Sambanthamurthi and Hayes KC

Addition of clinically-relevant levels of 3′-Azido-3′-deoxythymidine (AZT) to cultured HepG2 cells increases the number of reactive radical species (reactive oxygen and nitrogen species [ROS and RNS]) as well as random mutations in mitochondrial DNA (mtDNA). Co-treatment of AZT-exposed cells with palm fruit juice (PFJ) mitigates AZT mutagenesis. These findings suggest that AZT-dependent mtDNA damage resulted from increased reactive species and that PFJ, a known anti-oxidant, mitigated such damage by decreasing the levels of these species. The present report tests the predictions that (1) PFJ mitigates AZT mutagenesis by reducing the burden of AZT-induced reactive species, and (2) AZT-induced mutations in mtDNA should predominantly consist of G → T and C → A substitutions characteristic of DNA oxidative damage. Levels of reactive species and mitochondrial mutagenesis were measured in HepG2 cells exposed AZT in the presence or absence of PFJ. Controls experiments showed that PFJ in HepG2 cells exhibited strong scavenging activity against hydrogen peroxide-induced ROS, the main reactive species generated by dysfunctional mitochondria. Despite this strong antioxidant activity PFJ did not decrease AZT-induced reactive species at a concentration that mitigated mtDNA mutations. Consistent with this observation, the spectrum of AZT-induced mutations did not fit the spectrum expected from direct mtDNA oxidative damage. Instead, the spectrum obtained was consistent with the majority of mutations (80%) arising from mitochondrial DNA polymerase errors induced by AZT. These observations suggest that oxidative damage was not the major contributor to AZT-induced mutations.

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