Induction of a permeability transition in rat kidney mitochondria by pentachlorobutadienyl cysteine: a beta-lyase-independent process.
A Ca2+-dependent inner mitochondrial membrane permeability transition is induced by a number of agents, an effect which is thought to cause cytotoxicity. This transition involves formation of a pore allowing the passage of solutes of up to 1500 Da; it is blocked by cyclosporine A and Ca2+ chelating agents. The mitochondrial nephrotoxicant S-(1,2,3,4, 4-pentachlorobutadienyl)-L-cysteine (PCBC) caused collapse of the mitochondrial membrane potential, Ca2+-independent oxidation of pyridine nucleotides and release of accumulated Ca2+ in isolated rat kidney mitochondria, three hallmarks of the permeability transition. These effects were blocked by cyclosporine A and by ethylene glycol bis(beta-aminoethyl ether) tetraacetic acid (EGTA). Furthermore, EGTA was capable of reversing the collapse of the membrane potential. These data indicate that PCBC induced an inner membrane permeability transition. Interestingly, addition of aminoxyacetic acid, a beta-lyase inhibitor, did not prevent the permeability transition, and a nonmetabolizable analog of PCBC, S-(1,2,3,4, 4-pentachlorobutadienyl)-L-alpha-methyl cysteine, induced the permeability transition. Thus PCBC may act to induce the permeability transition through a mechanism that does not require metabolism by a beta-lyase. Since metabolism by a beta-lyase is required for PCBC toxicity, it is not clear that the permeability transition is involved in cysteine conjugate-mediated renal cell injury.
Brown
P C
PC
University Program in Toxicology, University of Maryland, 660 W. Redwood Street, Baltimore, Maryland, 21201, USA.
Sokolove
P M
PM
McCann
D J
DJ
Stevens
J L
JL
Jones
T W
TW
D000111:Acetylcysteine / Q000031:analogs & derivatives* / Q000633:toxicity; D000818:Animals; D002070:Butadienes / Q000633:toxicity*; D002118:Calcium / Q000378:metabolism*; D013437:Carbon-Sulfur Lyases; D007425:Intracellular Membranes / Q000187:drug effects / Q000502:physiology; D007668:Kidney / Q000187:drug effects / Q000648:ultrastructure; D008190:Lyases / Q000378:metabolism*; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects* / Q000201:enzymology; D008933:Mitochondrial Swelling / Q000187:drug effects*; D010539:Permeability / Q000187:drug effects; D051381:Rats; D011916:Rats, Inbred F344
D002070:Butadienes; C049739:N-acetyl-S-pentachloro-1,3-butadienylcysteine; D008190:Lyases; D013437:Carbon-Sulfur Lyases; C019969:S-alkylcysteine lyase; D002118:Calcium; D000111:Acetylcysteine