Mutagenicity of tetrachloroethene in the Ames test--metabolic activation by conjugation with glutathione.
The mutagenicity of tetrachloroethene (tetra) and its S conjugate, S-(1,2,2-trichlorovinyl)glutathione (TCVG) was investigated using a modified Ames preincubation assay. TCVG was a potent mutagen in presence of rat kidney particulate fractions containing high concentrations of gamma-glutamyl transpeptidase (GGT) and dipeptidases. Purified tetra was not mutagenic without exogenous metabolic activation or under conditions favoring oxidative metabolism. Preincubation of tetra with purified rat liver glutathione (GSH) S-transferases in presence of GSH and rat kidney fractions resulted in a time-dependent formation of TCVG as determined by (HPLC) analysis and in an unequivocal mutagenic response in the Ames test. Experiments with tetra in the isolated perfused rat liver demonstrated TCVG formation and its excretion with the bile; bile collected after the addition of tetra to the isolated perfused liver was unequivocally mutagenic in bacteria in the presence of kidney particulate fractions. The mutagenicity was reduced in all cases by the GGT inhibitor serine borate or the beta-lyase inhibitor aminooxyacetic acid. These results support the suggestion that cleavage of the GSH S conjugate formed from tetra by the enzymes of the mercapturic acid pathway and by beta-lyase may be involved in the nephrocarcinogenic effects of this haloalkene in rats.
Vamvakas
S
S
Institut für Toxikologie, Universität Würzburg, Federal Republic of Germany.
Herkenhoff
M
M
Dekant
W
W
Henschler
D
D
D000818:Animals; D001646:Bile / Q000378:metabolism; D001711:Biotransformation; D005978:Glutathione / Q000031:analogs & derivatives / Q000378:metabolism* / Q000493:pharmacokinetics / Q000633:toxicity; D005982:Glutathione Transferase / Q000378:metabolism; D066298:In Vitro Techniques; D008099:Liver / Q000378:metabolism; D008297:Male; D009152:Mutagenicity Tests; D009153:Mutagens / Q000493:pharmacokinetics; D010477:Perfusion; D051381:Rats; D011919:Rats, Inbred Strains; D012486:Salmonella typhimurium / Q000235:genetics; D013750:Tetrachloroethylene / Q000493:pharmacokinetics / Q000633:toxicity*
D009153:Mutagens; C060857:S-(1,2,2-trichlorovinyl)glutathione; D005982:Glutathione Transferase; D005978:Glutathione; D013750:Tetrachloroethylene