S-[(1 AND 2)-PHENYL-2-HYDROXYETHYL]CYSTEINE-INDUCED ALTERATIONS IN RENAL MITOCHONDRIAL-FUNCTION IN MALE FISCHER-344 RATS

Previous studies from our laboratory have shown that mitochondrial dys function may be an important early event in S-[(l and 2)-phenyl-2-hydr oxyethyl]cysteine (PHEC)-induced cytotoxicity in isolated rat renal pr oximal tubules. The present study has therefore examined in more detai l PHEC-induced mitochondrial dysfunction, both in vivo and in vitro, u sing isolated renal cortical mitochondria. Renal cortical mitochondria isolated from PHEC-treated rats in vivo showed depressed effects on t he mitochondrial respiration and oxidative phosphorylation in both a d ose (0, 250, and 500 mu mol/kg iv)- and time (0-24 h)-dependent manner in the presence of both succinate (Site 2) and malate plus a-ketoglut arate (Site 1) as respiratory substrates, with initial significant dep ression occurring as early as 4 h following treatment with 500 mu mol PHEC/kg, Similar mitochondrial dysfunctions were observed in vitro in concentration- and time-dependent manners with both respiratory substr ates. PHEC also caused a marked dose-dependent inhibition of mitochond rial succinate dehydrogenase and NADH cytochrome c reductase activitie s both in vivo and in vitro, with initial inhibition occurring as earl y as 4 h after in vivo administration and 45 min after exposure to PHE C in vitro, while the NADH dehydrogenase activity was not considerably inhibited. The mitochondrial ATPase activity was significantly decrea sed 4 and 24 h following treatment with PHEC (500 mu mol/kg). These re sults suggest that PHEC exerts its inhibitory effect on the mitochondr ial respiration and oxidative phosphorylation through the action on th e mitochondrial electron transport chain. PHEC significantly reduced t he activity of adenine nucleotide translocase as well as the net uptak e of substrates by mitochondria without affecting their efflux within 2-4 h after its injection (500 mu mol/kg). On the other hand, signific ant renal damage, as assessed by morphological study, appeared as earl y as 24 h following such treatment, The observation of similar effects after both in vivo and in vitro exposures may suggest that the effect on mitochondria may have a pathogenic role in PHEC-induced renal inju ry in rats. PHEC produces mitochondrial toxicity that results from an inactivation of mitochondrial anionic substrate transporters as well a s from an inhibition of activities of adenine nucleotide translocase a nd dehydrogenases. (C) 1998 Academic Press.