Nephrotoxicity mechanism of 1,1-dichloroethylene in mice.
Male Swiss OF1 mice were administered orally with a single dose (200 mg/kg) of 1,1-dichloroethylene (DCE). Examination of cryostat kidney sections stained for alkaline phosphatase (APP) revealed damage to about 50% of the proximal tubules at 8 h following DCE administration. Pretreatment with the anionic transport inhibitor probenecid by i.p., (0.75 mmol/kg, 30 min prior to and 10 min and 5 h following DCE administration) and with the gamma-glutamyltranspeptidase (GGT) inactivator acivicin by gavage and i.p. (50 mg/kg, 1 h and 30 min prior to DCE administration) failed to prevent DCE-induced renal toxicity. Pretreatment with the beta-lyase inactivator amino-oxyacetic acid (AOAA) by gavage (100 mg/kg, 30 min prior to and 10 min and 5 h following DCE administration), and with the renal cysteine conjugate S-oxidase inhibitor methimazole by i.p. (40 mg/kg, 30 min prior to DCE administration) reduced the number of damaged tubules by approximately 50 and 60%, respectively in mice treated with DCE. The results suggest that the DCE undergoes biotransformation by NADPH-cytochrome P450 to several reactive species which conjugate with glutathione (GSH). After arriving in the kidneys, the resulting conjugates reach the renal cells by a mechanism which depends on neither GGT, nor on an anionic transport system which is sensitive to probenecid. Once in the cells, the presumed GSH conjugates and/or their derivatives undergo secondary modification by beta-lyase and cysteine conjugate S-oxidase to reactive metabolite(s).
Ban
M
M
Service Toxicologie Industrielle Expérimentale, Institut National de Recherche et de Sécurité, Vandoeuvre, France.
Hettich
D
D
Huguet
N
N
Cavelier
L
L
D028341:Activins; D000284:Administration, Oral; D000469:Alkaline Phosphatase / Q000378:metabolism; D000625:Aminooxyacetic Acid / Q000494:pharmacology; D000818:Animals; D004000:Dichloroethylenes / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000633:toxicity*; D006133:Growth Substances / Q000494:pharmacology; D007265:Inhibins / Q000494:pharmacology; D007687:Kidney Tubules, Proximal / Q000187:drug effects* / Q000201:enzymology; D008297:Male; D008713:Methimazole / Q000494:pharmacology; D051379:Mice; D008815:Mice, Inbred Strains; D011339:Probenecid / Q000494:pharmacology
D004000:Dichloroethylenes; D006133:Growth Substances; D028341:Activins; D000625:Aminooxyacetic Acid; C029297:vinylidene chloride; D008713:Methimazole; D007265:Inhibins; D000469:Alkaline Phosphatase; D011339:Probenecid