S-(chloroethyl)-cysteine (CEC) and S-(1,2-dichlorovinyl)cysteine (DCVO) have been proposed as intermediates in the metabolic transformation of the carcinogens 1,2-dichloroethane and 1,1,2-trichloroethylene. We have tested the ability of CEC and DCVC to induce DNA repair and genotoxic effects at the chromosomal level by comparative assessment of unscheduled DNA synthesis induction and micronucleus formation in Syrian hamster embryo fibroblasts. CEC induced a potent and dose-dependent response in both assays, whereas DCVC treatment resulted in a comparatively weak induction of DNA repair and failed to raise micronucleus formation above control rates. Inhibition of cysteine conjugate \gB-lyase diminished the effect of DCVC, but had no influence on the genotoxicity of CEC either in the unscheduled DNA synthesis or micronucleus assay.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
Abbreviations
- AOAA:
-
aminooxyacetic acid
- CEC:
-
S-(chloroethyl)-cysteine; \gB-lyase, cysteine conjugate β-lyase
- DCE:
-
1,2-dichloroethane
- DCVC:
-
S(1,2-dichlorovinyl)-cysteine
- GSH:
-
glutathione
- HU:
-
hydroxyurea
- IBR:
-
IBR-modified Dulbecco's Eagle's reinforced medium
- MN2:
-
micronuclei/2,000 cells
- 4-NQO:
-
4-nitroquinoline-1-oxide
- SHE:
-
Syrian hamster embryo fibroblasts; 3H-Thd, 3H-thymidine
- TCE:
-
1,1,2-trichloroethylene
- UDS:
-
unscheduled DNA synthesis
References
CHASSEAYD, L.F. (1979). The role of glutathione and glutathione S-transferases in the metabolism of chemical carcinogens and other electrophilic agents. Adv. Cancer Res. 29:175–274.
DEKANT, W., METZLER, M. and HENSCHLER, D. (1986). Identification of S-1,2-dichlorovinyl-N-acetylcysteine as a urinary metabolite of Trichloroethylene. A possible explanation for its nephrocarcinogenicity in rats. Biochem. Pharm. 35:2455–2460.
DEKANT, W., VAMVAKAS, S., BERTHOLD, K., SCHMIDT, S., WILD, D. and HENSCHLER, D. (1986). Bacterial β-lyase mediated cleavage and mutagenicity of cysteine conjugates derived from the nephrocarcinogenic alkenes trichloroethylene, tetrachloroethylene and hexachlorobutadiene. Chem.-Biol. Interact. 60:31–45.
DOHN, D.R. and CASIDA, J.E.. (1987). Thiiranium Ion Intermediates in the Formation and Reactions of S-(2-Haloethyl)-L-cysteines. Bioorganic Chemistry 15:115–124.
GREEN, T. and ODUM, J. (1985). Structure/activity studies of the nephrotoxic and mutagenic action of cysteine conjugates of chloro- and fluoroalkenes. Chem.-Biol. Interact. 54:15–31.
GUENGERICH, F.P., CRAWFORD, W.W., Jr., DOMORAADZI, Y.Y., MacDONALD, T.L. and WATANABE, P.G. (1980). In vitro activation of 1,2-dichloroethane by microsomal and cytosolic enzymes. Toxicol. Appl. Pharmacol. 55:303–317.
HEDDLE, J.A., RAJ, A.S. and KREPINSKY, A.B. (1981). The micronucleus assay. II. In vitro. In: Stich, H. F. and San, R.H.C. (eds.). Short-term tests for chemical carcinogens, pp. 250–254. Springer Verlag, NY.
PIENTA, R.J. (1980). Transformation of Syrian hamster embryo cells by diverse chemicals and correlation with their reported carcinogenic and mutagenic activities. In: DeSerres, F.J. (ed.). Chemical Mutagens, Vol. 6, pp. 175–202, Plenum Publishing Corp., NY.
RANNUNG, U., SUDVALL, A. and RAMEL, C. (1978). The mutagenic effect of 1,2-dichloroethane on Salmonella typhimurium. I. Activation through conjugation with glutathione in vitro. Chem.-Biol. Interact. 20:1–16.
RANNUNG, U. and BEIJE, R. (1979). The mutagenic effect of 1,2-dichloroethane on Salmonella typhimurium. II. Activation by the isolated perfused liver. Chem.-Biol. Interact. 24:265–285.
SCHEITHAUER, C.S. and MAYER, R. (1979). Thio- and dithiocarboxylic acids and their derivatives. In: Seunig, A. (ed.). Topics in sulfur chemistry, Vol. 4, Thieme Verlag, Stuttgart.
SCHIFFMANN, D., REICHERT, D. and HENSCHLER, D. (1984). Induction of unscheduled DNA synthesis in Syrian hamster embryo fibroblasts by hexachlorobutadiene and its putative metabolite pentachlorobutenoic acid. Cancer Lett. 23:297–305.
SCHMID, W. (1977). The micronucleus test. In: Kilbey, B.J., Legator, M., Nichols, W., and Ramel, C. (eds.). Handbook of Mutagenicity Test Procedures, pp. 235–243, Elsevier, Amsterdam.
SCHMUCK, G., LIEB, G., SCHIFFMANN, D., WILD, D. and HENSCHLER, D. (1988). Characterization of a micronucleus assay with Syrian hamster embryo fibroblasts. Mut. Res. (in press).
SEYBOLD, G. (1975). Aliphatische Thiocarbonsäurechloride. Darstellung und Eigenschaften. Angewandte Chemie 87:710–711.
TSUTSUI, T., SUZUKI, N., MAIZUMI, H. and BARRET, J.C. (1984). Characterization of an unscheduled DNA synthesis assay with Syrian hamster embryo cells. Mut. Res. 129:111–117.
VADI, H.V., SCHASTEEN, C.S. and REED, D.J. (1985). Interactions of S-(2-haloethyl)mercapturic acid analogs with plasmid DNA. Toxicol. Appl. Pharmacol. 80:386–396.
VAMVAKAS, S., BERTHOLD, K., DEKANT, W. and HENSCHLER, D. (1988). Bacterial cysteine conjugate β-lyase and the metabolism of cysteine S-conjugates: Structural requirements for the cleavage of S-conjugates and the formation of reactive intermediates. Chem.-Biol. Interact. 65:59–71.
WALLACH, D.P. (1961). Studies on the GABA pathway 1. The inhibition of -aminobutyric acid -ketoglutaric acid transaminase in vitro and in vivo by U-7524 (amino-oxyacetic acid). Biochem. Pharmacol. 5:323–331.
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Vamvakas, S., Dekant, W., Schiffmann, D. et al. Induction of unscheduled DNA synthesis and micronucleus formation in Syrian hamster embryo fibroblasts treated with cysteine S-conjugates of chlorinated hydrocarbons. Cell Biol Toxicol 4, 393–403 (1988). https://doi.org/10.1007/BF00117768
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1007/BF00117768