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 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.
Barshteyn
Nella
N
Department of Comparative Biosciences and Division of Pharmaceutical Sciences, University of Wisconsin, Madison, Wisconsin 53706, USA.
Elfarra
Adnan A
AA
D000595:Amino Acid Sequence; D000818:Animals; D002851:Chromatography, High Pressure Liquid; D003432:Cross-Linking Reagents / Q000737:chemistry*; D003545:Cysteine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000097:blood / Q000737:chemistry / Q000633:toxicity; D004912:Erythrocytes / Q000378:metabolism; D005914:Globins / Q000737:chemistry*; D008297:Male; D008969:Molecular Sequence Data; D010455:Peptides / Q000737:chemistry; D051381:Rats; D017207:Rats, Sprague-Dawley; D021241:Spectrometry, Mass, Electrospray Ionization; D013871:Thiones / Q000097:blood* / Q000737:chemistry; D014241:Trichloroethylene / Q000737:chemistry / Q000378:metabolism; D014357:Trypsin / Q000378:metabolism
C545883:2-chlorothionoacetyl chloride; D003432:Cross-Linking Reagents; D010455:Peptides; C534676:S-(1,2-dichlorovinyl)-L-cysteine sulfoxide; D013871:Thiones; C545882:chlorothioketene; D014241:Trichloroethylene; C039961:S-(1,2-dichlorovinyl)cysteine; D005914:Globins; D014357:Trypsin; D003545:Cysteine
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