3'-AZIDO-3'-DEOXYTHYMIDINE UPTAKE INTO ISOLATED RAT-LIVER MITOCHONDRIA AND IMPAIRMENT OF ADP ATP TRANSLOCATOR/

To gain some insight into the mechanism by which 3'-azido-3'-deoxythym idine (AZT) impairs mitochondrial metabolism, [C-14]AZT uptake by rat liver mitochondria (RLM) in vitro was investigated. AZT accumulated in mitochondria in a time-dependent manner and entered the mitochondrial matrix. The rate of AZT uptake into mitochondria showed a hyperbolic dependence on the drug concentration and was inhibited by mersalyl, a thiol reagent that cannot enter mitochondria, thus showing that a memb rane protein is involved in AZT transport. Investigation into the capa bility of AZT to affect certain mitochondrial carriers demonstrated th at AZT was able to impair the ADP/ATP translocator, but had no effect on Pi, dicarboxylate, tricarboxylate, or oxodicarboxylate carriers. AZ T inhibited ADP/ATP antiport in either mitochondria or mitoplasts in a competitive manner with different sensitivity (K-i values were 18.3 /- 2.9 and 70.2 +/- 5.8 mu M, respectively). Consistent with this were isotopic measurements showing that AZT accumulates in the intermembra ne space. AZT does not use ADP/ATP carrier to enter mitochondria, as s hown by the failure of both carboxyatractyloside (CAT) to inhibit AZT transport into mitochondria and AZT to induce ATP efflux from ATP-load ed mitochondria. ADP/ATP translocator impairment by AZT as one of the biochemical processes responsible for the ATP deficiency syndrome is d iscussed. (C) 1997 Elsevier Science Inc.