| 19694420 |
Barshteyn N, Elfarra AA: Globin monoadducts and cross-links provide evidence for the presence of S-(1,2-dichlorovinyl)-L-cysteine sulfoxide, chlorothioketene, and 2-chlorothionoacetyl chloride in the circulation in rats administered S-(1,2-dichlorovinyl)-L-cysteine. Chem Res Toxicol. 2009 Sep;22(9):1629-38.
S-(1,2-Dichlorovinyl)-L-cysteine (DCVC), a mutagenic and nephrotoxic metabolite of trichloroethylene, is bioactivated to S-(1,2-dichlorovinyl)-L-cysteine sulfoxide (DCVCS) and chlorothioketene and/or 2-chlorothionoacetyl chloride by cysteine conjugate S-oxidase (S-oxidase) and cysteine conjugate beta-lyase (beta-lyase), respectively. Previously, we identified DCVCS-globin monoadducts and cross-links upon treating rats with DCVCS or incubating erythrocytes with DCVCS. In this study, the formation of DCVC-derived reactive intermediates was investigated after rats were given a single (230 or 460 micromol/kg, i.p.) or multiple (3 or 30 micromol/kg daily for 5 days) DCVC doses. LC/ESI/MS of trypsin-digested globin peptides revealed both S-oxidase and beta-lyase-derived globin monoadducts and cross-links consistent with in vivo DCVC bioactivation by both pathways. MS/MS analyses of trypsin-digested fractions of globin from one of the rats treated with multiple 30 micromol/kg DCVC doses led to identification of beta-lyase-derived monoadducts on both Cys93 and Cys125 of the beta-chains. While rats dosed with the 230 micromol/kg DCVC dose exhibited beta-lyase-dependent monoadducts and cross-links only (four out of four rats), rats given the 460 micromol/kg DCVC dose (two out of four) and rats administered the multiple DCVC doses (two out of four) exhibited both beta-lyase- and S-oxidase-derived monoadducts and cross-links. Because previous incubations of erythrocytes with DCVC did not result in detection of DCVCS-derived monoadducts or cross-links and had only resulted in detection of beta-lyase-derived monoadducts and cross-links, the DCVCS-globin monoadducts and cross-links detected in this study are likely the result of DCVC bioactivation outside the circulation and subsequent translocation of DCVCS and N-acetylated DCVCS into the erythrocytes. |
81(1,1,1,1) |