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Antimicrobial Agents and Chemotherapy, July 2007, p. 2531-2539, Vol. 51, No. 7
0066-4804/07/$08.00+0     doi:10.1128/AAC.00039-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Absence of a Universal Mechanism of Mitochondrial Toxicity by Nucleoside Analogs

Department of Biochemistry and Molecular Biology, Toxicology Graduate Program, University of Minnesota Medical School Duluth, Duluth, Minnesota

Received 11 January 2007/ Returned for modification 8 March 2007/ Accepted 24 April 2007

Nucleoside analogs are associated with various mitochondrial toxicities, and it is becoming increasingly difficult to accommodate these differences solely in the context of DNA polymerase gamma inhibition. Therefore, we examined the toxicities of zidovudine (AZT) (10 and 50 µM; 2.7 and 13.4 µg/ml), didanosine (ddI) (10 and 50 µM; 2.4 and 11.8 µg/ml), and zalcitabine (ddC) (1 and 5 µM; 0.21 and 1.1 µg/ml) in HepG2 and H9c2 cells without the presumption of mitochondrial DNA (mtDNA) depletion. Ethidium bromide (EtBr) (0.5 µg/ml; 1.3 µM) was used as a positive control. AZT treatment resulted in metabolic disruption (increased lactate and superoxide) and increased cell mortality with decreased proliferation, while mtDNA remained unchanged or increased (HepG2 cells; 50 µM AZT). ddC caused pronounced mtDNA depletion in HepG2 cells but not in H9c2 cells and increased mortality in HepG2 cells, but no significant metabolic disruption in either cell type. ddI caused a moderate depletion of mtDNA in both cell types but showed no other effects. EtBr exposure resulted in metabolic disruption, increased cell mortality with decreased cell proliferation, and mtDNA depletion in both cell types. We conclude that nucleoside analogs display unique toxicities within and between culture models, and therefore, care should be taken when generalizing about the mechanisms of nucleoside reverse transcriptase inhibitor toxicity. Additionally, mtDNA abundance does not necessarily correlate with metabolic disruption, especially in cell culture; careful discernment is recommended in this regard.

Published ahead of print on 30 April 2007.

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