Numerous studies have reported effects of
antiviral nucleoside analogs on mitochondrial function, but they have not correlated well with the observed toxic side effects. By comparing the effects of the five Food and Drug Administration-approved anti-human immunodeficiency virus
nucleoside analogs,
zidovudine (3'-azido-3'-deoxythymidine) (AZT),
2',3'-dideoxycytidine (ddC), 2', 3'-dideoxyinosine (ddI), 2',3'-didehydro-2',3'-deoxythymidine (
d4T), and beta-L-2',3'-dideoxy-3'-thiacytidine (3TC), as well as the metabolite of AZT,
3'-amino-3'-deoxythymidine (AMT), on mitochondrial function in a human
hepatoma cell line, this issue has been reexamined. Evidence for a number of
mitochondrial defects with AZT, ddC, and ddI was found, but only AZT induced a marked rise in
lactic acid levels. Only in mitochondria isolated from AZT (50 microM)-treated cells was significant inhibition of
cytochrome c oxidase and
citrate synthase found. Our investigations also demonstrated that AZT,
d4T, and 3TC did not affect the synthesis of the 11
polypeptides encoded by
mitochondrial DNA, while ddC caused 70% reduction of total
polypeptide content and ddI reduced by 43% the total content of 8
polypeptides (including
NADH dehydrogenase subunits 1, 2, 4, and 5,
cytochrome c oxidase subunits I to III, and
cytochrome b). We hypothesize that in hepatocytes the reserve capacity for mitochondrial respiration is such that inhibition of respiratory
enzymes is unlikely to become critical. In contrast, the combined inhibition of the citric acid cycle and electron transport greatly enhances the dependence of the cell on glycolysis and may explain why apparent
mitochondrial dysfunction is more prevalent with AZT treatment.