Disruption of mitochondrial energetics and DNA synthesis by the anti-AIDS drug dideoxyinosine.
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 of 0.40 +/- 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 ddI 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.
Youssef
J A
JA
Division of Pharmacology, University of Missouri-Kansas City 64108-2792.
Badr
M Z
MZ
D000818:Animals; D004247:DNA / Q000096:biosynthesis*; D016049:Didanosine / Q000633:toxicity*; D008297:Male; D008930:Mitochondria, Liver / Q000187:drug effects* / Q000378:metabolism; D010101:Oxygen Consumption; D051381:Rats; D011919:Rats, Inbred Strains; D013936:Thymidine / Q000378:metabolism
D004247:DNA; D016049:Didanosine; D013936:Thymidine