DIFFERENTIAL-EFFECTS OF ZIDOVUDINE AND ZIDOVUDINE TRIPHOSPHATE ON MITOCHONDRIAL PERMEABILITY TRANSITION AND OXIDATIVE-PHOSPHORYLATION

1 The effects of zidovudine (ZDV) and zidovudine triphosphate (ZDV-3P) on Ca2+-induced mitochondrial permeability transition (MPT), respirat ory control ratio (RCR) and ATP synthesis have been investigated on is olated rat liver mitochondria. 2 ZDV slightly but significantly decrea sed RCR and ATP synthesis but was ineffective in inhibiting MPT. In co ntrast, ZDV-3P did not alter RCR and ATP synthesis but strongly inhibi ted MPT (IC50 = 3.0 +/- 0.9 mu M). 3 The effect of ZDV-3P on mitochond rial swelling required a preincubation time. When incubated 10 min wit h mitochondria, ZDV-3P (8 mu M) totally inhibited the rate of swelling . 4 ADP, ATP and atractyloside, which are agents known to interact wit h the mitochondrial adenine nucleotide carrier (ANC), antagonized the effect of ZDV-3P on mitochondrial swelling. Indeed, the IC50 value of ZDV-3P increased from 3.0 to 17.4, 93.6 and 66.5 mu M, in the presence of 20 mu M, ADP, ATP or atractyloside, respectively. 5 ZDV-3P did not displace [H-3]-ATP from its mitochondrial binding site(s) whereas ADP and atractyloside did, suggesting that ZDV-3P and [H-3]-ATP do not sh are the same binding sites. 6 ZDV-3P did not affect either mitochondri al respiration or ATP synthesis but inhibited Ca2+-dependent mitochond rial swelling. It was concluded that mitochondrial toxic effects obser ved during the chronic administration of ZDV cannot be related to its active metabolite (ZDV-3P).