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.