A mechanism of S-(1,2,3,4,4-pentachloro-1,3-butadienyl)-L-cysteine toxicity to rabbit renal proximal tubules.
S-(1,2,3,4,4-Pentachloro-1,3-butadienyl)-L-cysteine (PCBC) has been identified as the penultimate compound responsible for hexachlorobutadiene-induced nephrotoxicity. The primary goal of these studies was to determine the mechanism of PCBC-induced toxicity in rabbit renal proximal tubules by examining the early changes in tubular physiology. PCBC (20-500 microM) induced a specific sequence of toxic events. Following 15 min of exposure, 200 microM PCBC increased basal (25%) and ouabain-insensitive (78%) respiration. This was followed by a decrease in basal (46%), nystatin-stimulated (54%), and ouabain-insensitive (21%) respiration and a decrease in glutathione content (79%). Finally, there was a decrease in cell viability as measured by a decrease in LDH retention at 60 min. Direct probing of mitochondrial function revealed that the initial increase in respiration resulted from the uncoupling of oxidative phosphorylation, while the late changes in respiration appeared to result from gross mitochondrial damage characterized by inhibited state 3 respiration, inhibited cytochrome c-cytochrome oxidase, and inhibited electron transport. Studies utilizing tubules with decreased glutathione content revealed that glutathione plays little if any role in the early events of PCBC-induced toxicity. These results suggest that PCBC-induced mitochondrial dysfunction may initiate the renal proximal tubule injury.
Schnellmann
R G
RG
Department of Pharmacology, College of Veterinary Medicine, University of Georgia, Athens 30602.
Lock
E A
EA
Mandel
L J
LJ
D000818:Animals; D002070:Butadienes / Q000378:metabolism* / Q000633:toxicity*; D003545:Cysteine / Q000031:analogs & derivatives* / Q000633:toxicity; D004305:Dose-Response Relationship, Drug; D005260:Female; D005978:Glutathione / Q000032:analysis / Q000378:metabolism*; D066298:In Vitro Techniques; D007687:Kidney Tubules, Proximal / Q000187:drug effects*; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008928:Mitochondria / Q000187:drug effects; D010085:Oxidative Phosphorylation / Q000187:drug effects; D010101:Oxygen Consumption / Q000187:drug effects; D011817:Rabbits
D002070:Butadienes; C039330:S-pentachlorobuta-1,3-dien-yl-cysteine; C001335:hexachlorobutadiene; D007770:L-Lactate Dehydrogenase; D005978:Glutathione; D003545:Cysteine