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

Mutat Res. 2003 Aug 5;539(1-2):157-66. doi: 10.1016/s1383-5718(03)00160-8.

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.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Chlorofluorocarbons / toxicity*
  • Cysteine / metabolism*
  • Glutathione / metabolism*
  • Mutagenicity Tests
  • Mutagens*
  • Salmonella typhimurium / drug effects
  • Salmonella typhimurium / genetics
  • Tetrachloroethylene / analogs & derivatives*
  • Tetrachloroethylene / toxicity*
  • Trichloroethylene / analogs & derivatives*
  • Trichloroethylene / toxicity*

Substances

  • Chlorofluorocarbons
  • Mutagens
  • trichlorofluoroethene
  • Trichloroethylene
  • 1,1,2-trichloro-3,3,3-trifluoro-1-propene
  • Glutathione
  • Cysteine
  • Tetrachloroethylene