Toxicity of S-pentachlorobutadienyl-L-cysteine studied with isolated rat renal cortical mitochondria.
The subcellular mechanism of alkenyl halide S-conjugate-induced nephrotoxicity was studied in mitochondria isolated from rat kidney cortex in vitro using the cysteine conjugate of hexachloro-1,3-butadiene, i.e., S-pentachlorobutadienyl-L-cysteine (PCBC) as a model substrate. Respiring mitochondria exposed to various concentrations of PCBC exhibited a dose-dependent loss of ability to retain calcium. This phenomenon was associated with a sudden collapse of the mitochondrial membrane potential. PCBC caused a slow nonenzymatic depletion of mitochondrial glutathione. This was not due to oxidation or formation of mixed disulfides, and was efficiently counteracted by preincubation with aminooxyacetic acid, an inhibitor of cysteine-conjugate beta-lyase activity. PCBC inhibited state 3 respiration in the presence of succinate as substrate, which indicates that the activity of succinate dehydrogenase was affected. Thus, the present data confirm that impairment of mitochondrial function is a feature of nephrotoxicity mediated by alkenyl halide S-conjugates. We suggest a pathway involving interaction of beta-lyase-dependent reactive metabolite with the mitochondrial inner membrane, loss of membrane potential, disturbance of Ca2+ homeostasis, and subsequent respiratory insufficiency as a mechanism for renal tubular cytotoxicity.
Wallin
A
A
Department of Forensic Medicine, Karolinska Institute, Stockholm, Sweden.
Jones
T W
TW
Vercesi
A E
AE
Cotgreave
I
I
Ormstad
K
K
Orrenius
S
S
D000625:Aminooxyacetic Acid / Q000494:pharmacology; D000818:Animals; D002070:Butadienes / Q000633:toxicity*; D002118:Calcium / Q000378:metabolism; D003545:Cysteine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000633:toxicity; D005978:Glutathione / Q000378:metabolism; D007425:Intracellular Membranes / Q000187:drug effects / Q000502:physiology; D007672:Kidney Cortex / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D007700:Kinetics; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism* / Q000502:physiology; D010101:Oxygen Consumption / Q000187:drug effects; D051381:Rats; D011919:Rats, Inbred Strains
D002070:Butadienes; D000625:Aminooxyacetic Acid; C039330:S-pentachlorobuta-1,3-dien-yl-cysteine; D005978:Glutathione; D003545:Cysteine; D002118:Calcium