alexa Oxidative Damage is not a Major Contributor to AZT-Induced Mitochondrial Mutations | OMICS International | Abstract
ISSN 2155-6113

Journal of AIDS & Clinical Research
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Research Article

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

Adam E Osborne1, J Aquiles Sanchez1*, Lawrence J Wangh1, Ravigadevi Sambanthamurthi2 and Hayes KC1

1Department of Biology, Brandeis University, Waltham, MA, 02454, USA

2Malaysian Palm Oil Board, Kajang, Selangor, Malaysia

*Corresponding Author:
Aquiles Sanchez J
Department of Biology, Brandeis University
Waltham, MA, 02454, USA
Tel: 1-781-736-3111
Fax: 1-781-736-3107
E-mail: [email protected]

Received date: January 05, 2015; Accepted date: March 14, 2015; Published date: March 24, 2015

Citation: Osborne AE, Sanchez JA, Wangh LJ, Sambanthamurthi R, Hayes KC (2015) Oxidative Damage is not a Major Contributor to AZT-Induced Mitochondrial Mutations. J AIDS Clin Res 6:441. doi:10.4172/2155-6113.1000441

Copyright: © 2015 Osborne AE, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Abstract

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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