title: Mutagenicity of the glutathione and cysteine S-conjugates of the haloalkenes 1,1,2-trichloro-3,3,3-trifluoro-1-propene and trichlorofluoroethene in the Ames test in comparison with the tetrachloroethene-analogues.
abstract: The nephrotoxic and nephrocarcinogenic potential of the haloalkenes is associated with the conjugation of the chemicals to L-glutathione. Subsequent processing of the haloalkene glutathione S-conjugates via the cysteine conjugate beta-lyase pathway in the mammalian kidney yields nephrotoxic and mutagenic species. To investigate whether S-conjugates of the model chlorofluoroalkenes 1,1,2-trichloro-3,3,3-trifluoro-1-propene (CAS # 431-52-7) and trichlorofluoroethene (CAS # 359-29-5) show comparable effects, we have synthesised the respective cysteine and glutathione S-conjugates and subjected them to the Ames test. The cysteine and glutathione S-conjugates of tetrachloroethene (CAS # 127-18-4), S-(1,2,2-trichlorovinyl)-L-cysteine (TCVC) and S-(1,2,2-trichlorovinyl)glutathione (TCVG) were used as positive controls and reference substances. S-(1,2-dichloro-3,3,3-trifluoro-1-propenyl)-L-cysteine (DCTFPC) and S-(2,2-dichloro-1-fluorovinyl)-L-cysteine (DCFVC) showed clear dose-dependent mutagenic effects with the Salmonella typhimurium tester strains TA100 and TA98. Using TCVC as a reference substance the following ranking in mutagenic response was established: TCVC>DCTFPC>DCFVC. S-(1,2-dichloro-3,3,3-trifluoro-1-propenyl)glutathione (DCTFPG) and S-(2,2-dichloro-1-fluorovinyl)glutathione (DCFVG) showed potent dose-dependent mutagenic effects with the S. typhimurium tester strain TA100 in the presence of a rat kidney S9-protein fraction; tests carried out in the absence of the bioactivation system resulted only in background rates of revertants. Using TCVG as a reference substance the following ranking in mutagenic response was established: TCVG=DCTFPG>DCFVG. The data obtained provide a basis for further studies on the mutagenic and presumable carcinogenic potential of the substances.
authors.affiliation: Department of Occupational & Social Medicine, Abteilung Arbeits-und Sozialmedizin, Georg-August-Universität Göttingen, Waldweg 37, D-37073 Göttingen, Germany.
authors.forename: Birte
authors.initials: B
authors.lastname: Dreessen
authors.forename: Götz
authors.initials: G
authors.lastname: Westphal
authors.forename: Jürgen
authors.initials: J
authors.lastname: Bünger
authors.forename: Ernst
authors.initials: E
authors.lastname: Hallier
authors.forename: Michael
authors.initials: M
authors.lastname: Müller
mesh_terms: D017402:Chlorofluorocarbons / Q000633:toxicity*; D003545:Cysteine / Q000378:metabolism*; D005978:Glutathione / Q000378:metabolism*; D009152:Mutagenicity Tests; D009153:Mutagens; D012486:Salmonella typhimurium / Q000187:drug effects / Q000235:genetics; D013750:Tetrachloroethylene / Q000031:analogs & derivatives* / Q000633:toxicity*; D014241:Trichloroethylene / Q000031:analogs & derivatives* / Q000633:toxicity*
chemical_list: D017402:Chlorofluorocarbons; D009153:Mutagens; C439617:trichlorofluoroethene; D014241:Trichloroethylene; C060270:1,1,2-trichloro-3,3,3-trifluoro-1-propene; D005978:Glutathione; D003545:Cysteine; D013750:Tetrachloroethylene