In vitro dipeptide, nucleoside, and glutathione alkylation by S-(2-chloroethyl)glutathione and S-(2-chloroethyl)-L-cysteine.
S-(2-Chloroethyl)glutathione (CEG) and S-(2-chloroethyl)-L-cysteine (CEC) are putative glutathione-dependent metabolites of 1,2-dichloroethane bioactivation and have been shown to be direct-acting alkylating agents. A group of dipeptides, nucleosides, and glutathione were used as model compounds to investigate CEG and CEC alkylation events. The extent of glutathione and cysteinyltyrosine alkylation was much greater than histidyltyrosine greater than lysyltyrosine, glycyltyrosine, glycyltryptophan, and 2'-deoxyguanosine greater than 2'-deoxyadenosine, 2'-deoxycytidine, and thymidine for both CEG and CEC. The rate of S-alkylation of cysteinyltyrosine by CEG and CEC occurred at rates 54 and 72 times that for the N7 position of 2'-deoxyguanosine and 16 and 10 times that for histidyltyrosine imidazole nitrogen, respectively. The rate of S-alkylation of glutathione by CEG was found to be 27% faster than that for S-alkylation of cysteinyltyrosine whereas S-alkylation of glutathione by CEC was 22% slower than that for cysteinyltyrosine. Both CEG and CEC demonstrated a selectivity for cysteinyl thiol alkylation over a wide variety of other nucleophilic sites. These findings demonstrate a wide range of functional group reactivity that should be taken into consideration when assessing the alkylation of cellular macromolecules by such glutathione-derived metabolites of the 1,2-dihaloethanes in vivo.
Jean
P A
PA
Department of Biochemistry and Biophysics, Oregon State University, Corvallis 97331-6503.
Reed
D J
DJ
D000478:Alkylation; D003545:Cysteine / Q000031:analogs & derivatives* / Q000737:chemistry; D004151:Dipeptides / Q000737:chemistry*; D005978:Glutathione / Q000031:analogs & derivatives* / Q000737:chemistry*; D007461:Iodoacetates / Q000737:chemistry; D019807:Iodoacetic Acid; D007700:Kinetics; D009682:Magnetic Resonance Spectroscopy; D009705:Nucleosides / Q000737:chemistry*
D004151:Dipeptides; D007461:Iodoacetates; D009705:Nucleosides; C072331:cysteinyltyrosine; C045285:S-(2-chloroethyl)cysteine; D005978:Glutathione; D003545:Cysteine; C046570:S-(2-chloroethyl)glutathione; D019807:Iodoacetic Acid