Disruption of mitochondrial energetics and DNA synthesis by the anti-AIDS drug dideoxyinosine

Abstract

The purpose of this study was to clarify the role of the mitochondria as a site for the reported hepatotoxic effects of the anti-AIDS drug dideoxyinosine (ddI). Data show that ddI interfered with the mitochondrial redox state in perfused livers leading to more oxidized mitochondria. This effect was reflected by a significant decrease in the mitochondrial NADH/NAD + ratios from basal values of0.40 ± 0.04 to 0.28 ± 0.02 within 10 min following the infusion of ddI. In suspensions of isolated mitochondria utilizing succinate as a substrate, ddI diminished state 3 and stimulated state 4 respiration significantly, suggesting an uncoupling effect by ddI. Incubation of mitochondria with ddI resulted in a significant decrease in the mitochondrial respiratory control ratios (state 3/state 4 respiration) to 0.8 ± 0.02 from corresponding control values of 6.0 ± 0.40. Data also show that ddl inhibited mitochondrial DNA synthesis as evidenced by the decrease in [ 3H]thymidine incorporation into mitochondrial DNA. This study confirms the need for a close monitoring of patients receiving the dideoxyinosine anti-AIDS drugs and for prompt discontinuation of these drugs before potential irreversible liver damage occurs.