Nephrotoxicity and hepatotoxicity of 1,1-dichloro-2,2-difluoroethylene in the rat. Indications for differential mechanisms of bioactivation.
1,1-Dichloro-2,2-difluoroethylene (DCDFE) produced marked nephrotoxicity in rats upon an i.p. dose of 150 mumole/kg. At doses higher than 375 mumole/kg, DCDFE also produced hepatotoxicity. Aminooxyacetic acid, an inhibitor of cysteine conjugate beta-lyase, appeared to be slightly nephrotoxic in Wistar rats. Nevertheless it exerted an inhibitory effect on the nephrotoxicity of DCDFE. The N-acetylcysteine conjugate of DCDFE was identified as a major urinary metabolite of DCDFE. When administered as such, this conjugate appeared to be a potent nephrotoxin, without any effect on the liver, indicating that glutathione conjugation of DCDFE is most likely a bioactivation step for nephrotoxicity. The appearance of traces of chlorodifluoroacetic acid in urine of rats treated with higher doses of DCDFE indicates the existence of an oxidative pathway of metabolism of DCDFE, probably involving epoxidation by hepatic mixed-function oxidases. It is speculated that the latter route might account for the hepatotoxicity at higher doses of DCDFE. The nephro- and hepatotoxicity of DCDFE, therefore, most likely are the result of two different mechanisms of bioactivation.
Department of Pharmacochemistry, Molecular Toxicology, Free University, Amsterdam, The Netherlands.
J N
JN
Commandeur
R A
RA
Oostendorp
P R
PR
Schoofs
B
B
Xu
N P
NP
Vermeulen
D000085:Acetates / Q000652:urine; D019342:Acetic Acid; D000625:Aminooxyacetic Acid / Q000494:pharmacology; D000818:Animals; D001711:Biotransformation; D056486:Chemical and Drug Induced Liver Injury / Q000209:etiology*; D017402:Chlorofluorocarbons; D003545:Cysteine / Q000031:analogs & derivatives / Q000652:urine; D004000:Dichloroethylenes / Q000378:metabolism / Q000633:toxicity* / Q000652:urine; D008401:Gas Chromatography-Mass Spectrometry; D006843:Hydrocarbons, Chlorinated / Q000633:toxicity*; D006845:Hydrocarbons, Fluorinated / Q000378:metabolism / Q000633:toxicity* / Q000652:urine; D006846:Hydrocarbons, Halogenated / Q000378:metabolism / Q000633:toxicity*; D007674:Kidney Diseases / Q000139:chemically induced*; D051381:Rats; D013329:Structure-Activity Relationship
D000085:Acetates; D017402:Chlorofluorocarbons; D004000:Dichloroethylenes; D006843:Hydrocarbons, Chlorinated; D006845:Hydrocarbons, Fluorinated; D006846:Hydrocarbons, Halogenated; D000625:Aminooxyacetic Acid; C054365:1,1-dichloro-2,2-difluoroethylene; D003545:Cysteine; D019342:Acetic Acid