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

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 mu mol/kg, i.p.) Or Multiple Q or 30,mu mol/kg daily for 5 days) DCVC doses. LC/ESI/MS of trypsin-digested globin peptides revealed both S-oxidase and P-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 front one of the rats treated with Multiple 30 mu mol/kg DCVC closes led to identification of beta-lyase-derived monoadducts on both Cys93 and Cys125 of the beta-chains. While rats dosed with the 230 mu mol/kg DCVC (lose exhibited beta-lyase-dependent monoadducts and cross-links only (four Out of four rats), rats given the 460 mu mol/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 P-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.