Effect of beta-naphthoflavone and phenobarbital on the nephrotoxicity of chlorotrifluoroethylene and 1,1-dichloro-2,2-difluoroethylene in the rat.
The role of cytochrome P450 activity in the nephrotoxicity of chlorotrifluoroethylene (CTFE) and 1,1-dichloro-2,2-difluoroethylene (DCDFE) was investigated in the male rat. Hepatic cytochrome P450 1A1 and principally P450 2B1/2 were induced by beta-naphthoflavone and phenobarbital, respectively. Nephrotoxicity was evaluated by investigating urine biochemical parameters, kidney histochemistry and histopathological modifications. Both CTFE and DCDFE induce severe nephrotoxicity in rats after 4 h of exposure to 200 and 100 ppm, respectively. Compared with controls, activity levels of gamma-glutamyltranspeptidase (gamma GT), aspartate aminotransferase (AST), alkaline phosphatase (ALP) and N-acetyl-beta-D-glucosaminidase (NAG) in 24-h urine were increased similarly, but urinary excretion of glucose, proteins and beta2-microglobulin (beta2-m) and serum urea and creatinine levels were increased. Histopathological and histochemical examinations of kidney sections of CTFE- and DCDFE-exposed rats revealed cellular necrosis and tubular lesions 24 h after exposure. Beta-naphthoflavone-pretreated rats were afforded some protection against the nephrotoxicity of CTFE and DCDFE. Phenobarbital did not modify DCDFE nephrotoxicity but afforded some protection against CTFE nephrotoxicity. In conclusion, CTFE and DCDFE are strong nephrotoxins. Cytochrome P450 1A1 is implicated in CTFE and DCDFE metabolism and one or several cytochromes induced by phenobarbital are implicated in CTFE metabolism. The P450 cytochromes involved in CTFE and DCDFE metabolism probably constitute detoxication metabolic pathways. The nephrotoxicity of CTFE and DCDFE is therefore subordinated to the cytochrome P450 activity involved in their metabolism.
Morel
Georges
G
Institut National de Recherche et de Sécurité, Avenue de Bourgogne, BP 27, 54501 Vandoeuvre, France. georges.morel@inrs.fr
Ban
Masarin
M
Bonnet
Pierre
P
Zissu
Danièle
D
Brondeau
Marie-Thérèse
MT
D000818:Animals; D017402:Chlorofluorocarbons / Q000378:metabolism / Q000633:toxicity* / Q000652:urine; D003577:Cytochrome P-450 Enzyme System / Q000187:drug effects / Q000378:metabolism*; D007674:Kidney Diseases / Q000139:chemically induced* / Q000473:pathology; D008297:Male; D010634:Phenobarbital / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D019324:beta-Naphthoflavone / Q000494:pharmacology*
D017402:Chlorofluorocarbons; D019324:beta-Naphthoflavone; C054365:1,1-dichloro-2,2-difluoroethylene; D003577:Cytochrome P-450 Enzyme System; C016304:chlorotrifluoroethylene; D010634:Phenobarbital