title: 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.
abstract: 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.
authors.affiliation: Department of Comparative Biosciences and Division of Pharmaceutical Sciences, University of Wisconsin, Madison, Wisconsin 53706, USA.
authors.forename: Nella
authors.initials: N
authors.lastname: Barshteyn
authors.forename: Adnan A
authors.initials: AA
authors.lastname: Elfarra
mesh_terms: 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
chemical_list: 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
references.citation: Arch Toxicol. 2000 Jul;74(4-5):207-14
references.pmid: 10959794
references.citation: Drug Metab Dispos. 1990 Jan-Feb;18(1):50-4
references.pmid: 2139845
references.citation: Chem Res Toxicol. 2003 Mar;16(3):320-7
references.pmid: 12641432
references.citation: Chem Res Toxicol. 1996 Jan-Feb;9(1):41-9
references.pmid: 8924615
references.citation: J Chromatogr A. 1999 Jun 25;847(1-2):25-34
references.pmid: 10431349
references.citation: J Biol Chem. 1990 Dec 15;265(35):21603-11
references.pmid: 2254317
references.citation: Anesthesiology. 1996 Dec;85(6):1454-61
references.pmid: 8968194
references.citation: Chem Res Toxicol. 1991 Nov-Dec;4(6):655-60
references.pmid: 1807449
references.citation: J Biochem. 1984 Jan;95(1):247-54
references.pmid: 6706912
references.citation: J Toxicol Environ Health A. 1999 Jan 8;56(1):1-21
references.pmid: 9923751
references.citation: Toxicol Appl Pharmacol. 2006 Mar 1;211(2):133-47
references.pmid: 16125744
references.citation: Proc Natl Acad Sci U S A. 1963 Oct;50:774-82
references.pmid: 14077510
references.citation: Amino Acids. 2006 Feb;30(1):1-15
references.pmid: 16463021
references.citation: Mol Pharmacol. 1997 Mar;51(3):507-15
references.pmid: 9058607
references.citation: Toxicol Appl Pharmacol. 1998 Nov;153(1):20-7
references.pmid: 9875296
references.citation: Chem Biol Interact. 2008 Mar 27;172(2):105-14
references.pmid: 18291356
references.citation: AAPS J. 2006 Mar 10;8(1):E101-11
references.pmid: 16584116
references.citation: Mutat Res. 1977 Nov;45(2):175-84
references.pmid: 593285
references.citation: Chem Res Toxicol. 2009 Jun;22(6):1163-71
references.pmid: 19419228
references.citation: Int J Hyg Environ Health. 2007 May;210(3-4):461-70
references.pmid: 17321211
references.citation: Chem Res Toxicol. 2009 Jul;22(7):1351-8
references.pmid: 19572755
references.citation: J Pharmacol Exp Ther. 2003 Jan;304(1):185-91
references.pmid: 12490590
references.citation: J Pharmacol Exp Ther. 2003 Jun;305(3):1163-72
references.pmid: 12626654
references.citation: J Biol Chem. 1986 May 5;261(13):5930-5
references.pmid: 3700378
references.citation: Toxicol Sci. 1999 Mar;48(1):5-13
references.pmid: 10330678
references.citation: J Agric Food Chem. 2008 Aug 13;56(15):6046-53
references.pmid: 18624432
references.citation: Drug Metab Dispos. 1999 Jan;27(1):46-52
references.pmid: 9884308
references.citation: Carcinogenesis. 1998 Sep;19(9):1565-71
references.pmid: 9771926
references.citation: Chem Res Toxicol. 2007 Oct;20(10):1563-9
references.pmid: 17892265
references.citation: Carcinogenesis. 1996 Dec;17(12):2661-71
references.pmid: 9006104
references.citation: Adv Pharmacol. 1994;27:115-62
references.pmid: 8068551
references.citation: Cancer Res. 1988 Sep 1;48(17):4756-61
references.pmid: 3409217
references.citation: J Pharmacol Exp Ther. 1994 Apr;269(1):374-83
references.pmid: 8169843
references.citation: J Biol Chem. 1991 Nov 25;266(33):22179-85
references.pmid: 1939239
references.citation: Toxicol Ind Health. 1994 Jan-Apr;10(1-2):103-12
references.pmid: 7570611
references.citation: Mutat Res. 1988 Sep;206(1):83-90
references.pmid: 2901035
references.citation: Arch Biochem Biophys. 2008 Jun 1;474(1):72-81
references.pmid: 18342615
references.citation: J Biol Chem. 2001 Mar 9;276(10):7004-10
references.pmid: 11096069
references.citation: Chem Res Toxicol. 1994 Nov-Dec;7(6):724-32
references.pmid: 7696525
references.citation: Chem Res Toxicol. 2008 Sep;21(9):1716-25
references.pmid: 18681461
references.citation: Biophys J. 1999 Jan;76(1 Pt 1):88-97
references.pmid: 9876125
references.citation: Drug Metab Dispos. 1995 Jan;23(1):124-8
references.pmid: 7720515
references.citation: J Chromatogr B Analyt Technol Biomed Life Sci. 2002 Oct 5;778(1-2):279-308
references.pmid: 12376136
references.citation: Chem Res Toxicol. 1995 Jun;8(4):580-5
references.pmid: 7548738
references.citation: Mol Pharmacol. 1987 Feb;31(2):208-12
references.pmid: 3807895
references.citation: Anal Chem. 2008 Nov 15;80(22):8799-806
references.pmid: 18947195
references.citation: Drug Metab Dispos. 2006 Jan;34(1):19-26
references.pmid: 16183778
references.citation: Arch Biochem Biophys. 1972 Nov;153(1):105-15
references.pmid: 4346629
references.citation: Chem Biol Interact. 2007 Mar 20;166(1-3):63-77
references.pmid: 16949064
references.citation: J Toxicol Environ Health. 1995 Dec;46(4):443-64
references.pmid: 8523471
references.citation: Arch Toxicol. 1996;70(6):338-46
references.pmid: 8975632
references.citation: J Mass Spectrom. 2001 Jan;36(1):47-57
references.pmid: 11180646
references.citation: Chem Res Toxicol. 2000 Nov;13(11):1103-13
references.pmid: 11087432