Mutagenicity and cytotoxicity of two regioisomeric mercapturic acids and cysteine S-conjugates of trichloroethylene.
The mutagenicity, cytotoxicity and metabolism of two regioisomic L-cysteine- and N-acetyl-L-cysteine-S-conjugates of trichloroethylene were studied. The 1,2-dichlorovinyl(1,2-DCV) isomers of both the cysteine conjugate and the mercapturate were much stronger mutagens in the Ames test with Salmonella typhimurium TA2638 when compared to the corresponding 2,2-dichlorovinyl (2,2-DCV) isomers. Similarly, the 1,2-DCV isomers were more cytotoxic towards isolated rat kidney proximal tubular cells, as assessed by inhibition of alpha-methylglucose uptake, than the 2,2-DCV isomers. The 3-4-fold higher rate of beta-lyase-dependent activation of S-(1,2-dichlorovinyl)-L-cysteine (1,2-DCV-Cys) when compared to S-(1,2-dichlorovinyl)-L-cysteine (2,2-DCV-Cys) as well as the different nature of the reactive intermediates formed is probably responsible for these structure-dependent effects. The cytotoxicity of N-acetyl-S-(1,2-dichlorovinyl)-L-cysteine (1,2-DCV-NAc) toward isolated kidney cells showed a delayed time course as compared to that of 1,2-DCV-Cys, probably due to the relatively low rate of deacetylation of 1,2-DCV-NAc. The time course of cytotoxicity of N-acetyl-S-(2,2-dichlorovinyl)-L-cysteine (2,2-DCV-NAc), however, parallelled that of 2,2-DCV-Cys. Due to the relatively high rate of N-acetylation and low rate of beta-lyase activation, for 2,2-DCV-Nac the beta-lyase activation step may be rate limiting. Different rates of cellular uptake also may play a role in time course of toxicity of the cysteine conjugates and the mercapturic acids in the renal cells.
Department of Pharmacochemistry (Division of Molecular Toxicology), Free University, Amsterdam, The Netherlands.
J N
JN
Commandeur
P J
PJ
Boogaard
G J
GJ
Mulder
N P
NP
Vermeulen
D000111:Acetylcysteine / Q000031:analogs & derivatives* / Q000633:toxicity*; D000818:Animals; D003545:Cysteine / Q000031:analogs & derivatives* / Q000633:toxicity; D066298:In Vitro Techniques; D007687:Kidney Tubules, Proximal / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D009152:Mutagenicity Tests; D009153:Mutagens; D051381:Rats; D011919:Rats, Inbred Strains; D012486:Salmonella typhimurium / Q000187:drug effects; D013237:Stereoisomerism; D014241:Trichloroethylene / Q000378:metabolism*
D009153:Mutagens; C049705:S-1,2-dichlorovinyl-N-acetylcysteine; D014241:Trichloroethylene; C039961:S-(1,2-dichlorovinyl)cysteine; D003545:Cysteine; D000111:Acetylcysteine