Mechanism of S-(1,2-dichlorovinyl)-L-cysteine- and S-(1,2-dichlorovinyl)-L-homocysteine-induced renal mitochondrial toxicity.
The mechanism by which the nephrotoxic S-conjugates S-(1,2-dichlorovinyl)-L-cysteine (DCVC) and S-(1,2-dichlorovinyl)-L-homocysteine (DCVHC) produce toxicity in rat kidney mitochondria was studied by examining their effects on mitochondrial function, structural integrity, and metabolism. Both S-conjugates inhibited succinate-linked state 3 respiration and impaired the ability of mitochondria to retain Ca2+ and to generate a membrane potential; 30-60 min were required for maximal expression of these functional changes. Mitochondrial structure was damaged, as indicated by enhanced polyethylene glycol-induced shrinkage of matrix volume and by leakage of protein and malic dehydrogenase from the matrix; 60-120 min were required for maximal expression of these structural changes. Much shorter incubation times (15-30 min) were required for DCVC and DCVHC to decrease ATP concentrations, to alter the concentrations of several citric acid cycle intermediates, and to inhibit succinate:cytochrome c oxidoreductase and isocitrate dehydrogenase activities. Lipid peroxidation and oxidation of glutathione to glutathione disulfide also occurred. The relative time courses of these pathological changes indicate that the initial effects of DCVC and DCVHC in renal mitochondria are the inhibition of energy metabolism and the oxidation of glutathione. These changes then lead to alterations in mitochondrial function and ultimately to irreversible damage to mitochondrial structure.
Lash
L H
LH
Department of Pharmacology, School of Medicine and Dentistry, University of Rochester, New York 14642.
Anders
M W
MW
D000255:Adenosine Triphosphate / Q000378:metabolism; D003545:Cysteine / Q000031:analogs & derivatives* / Q000633:toxicity; D005978:Glutathione / Q000378:metabolism; D006710:Homocysteine / Q000031:analogs & derivatives* / Q000633:toxicity; D007668:Kidney / Q000187:drug effects*; D008054:Lipid Peroxides / Q000378:metabolism; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism / Q000648:ultrastructure; D010085:Oxidative Phosphorylation / Q000187:drug effects; D010101:Oxygen Consumption / Q000187:drug effects
D008054:Lipid Peroxides; D006710:Homocysteine; C051126:S-(1,2-dichlorovinyl)homocysteine; C039961:S-(1,2-dichlorovinyl)cysteine; D000255:Adenosine Triphosphate; D005978:Glutathione; D003545:Cysteine