Interaction of S-(1,2-dichlorovinyl)-l-cysteine with proteins

Anderson, Paul N.; Schultze, Michael

doi:10.1016/0003-9861(65)90408-x

Cited by 25 publications

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References 20 publications

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“…The toxicity of cysteine S-conjugates of haloalkenes is directed to the proximal tubule of the kidney, due to the presence of active uptake mechanisms and the high activity of the bioactivating enzyme, cysteine S-conjugate β-lyase (β-lyase), in this part of the nephron ( , ). Cleavage of cysteine S-conjugates of haloalkenes by β-lyase results in the formation of reactive intermediates which may bind covalently to essential biomacromolecules, such as proteins, lipids, DNA, and RNA ( − ), thus initiating processes leading to cell death, mutagenicity, or carcinogenicity. Reactive intermediates which have been proposed for S -(2,2-dihalo-1,1-difluoroethyl)- l -cysteine and S -(trihalovinyl)- l -cysteine ( − ) are shown in Figure .…”

Section: Introductionmentioning

confidence: 99%

Bioactivation of S-(2,2-Dihalo-1,1-difluoroethyl)-l- cysteines and S-(Trihalovinyl)-l-cysteines by Cysteine S-Conjugate β-Lyase: Indications for Formation of both Thionoacylating Species and Thiiranes as Reactive Intermediates

Commandeur¹,

King²,

Koymans³

et al. 1996

Chem. Res. Toxicol.

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The covalent binding of reactive intermediates, formed by beta-elimination of cysteine S-conjugates of halogenated alkenes, to nucleophiles was studied using 19F-NMR and GC-MS analysis. beta-Elimination reactions were performed using rat renal cytosol and a beta-lyase model system, consisting of pyridoxal and copper(II) ion. S-(1,1,2,2-Tetrafluoroethyl)-L-cysteine (TFE-Cys) was mainly converted to products derived from difluorothionoacetyl fluoride, namely, difluorothionoacetic acid, difluoroacetic acid, and N-difluorothionoacetylated TFE-Cys. In the presence of o-phenylenediamine (OPD), as a bifunctional nucleophilic trapping agent, the major product formed was 2-(difluoromethyl)benzimidazole. This product results from initial reaction of difluorothionoacetyl fluoride with one of the amino groups of OPD, followed by a condensation reaction between the thionoacyl group and the adjacent amino group of OPD. In incubations with S-(2-chloro-1,1,2-trifluorofluoroethyl)-L-cysteine (CTFE-Cys) and S-(2,2-dichloro-1,1-difluorofluoroethyl)-L-cysteine (DCDFE-Cys), formation of thionoacylated cysteine S-conjugates was also observed by GC-MS analysis, indicating formation of the corresponding thionoacyl fluorides. However, according to 19F-NMR analysis, chlorofluorothionoacyl fluoride-derived products accounted for only 10% of the CTFE-Cys converted. In the presence of OPD, next to the corresponding 2-(dihalomethyl)benzimidazoles, 2-mercaptoquinoxaline was identified as the main product in incubations with CTFE-Cys. When chlorofluorothionoacylating species were generated from the unsaturated S-(2-chloro-1,2-difluorovinyl)-L-cysteine (CDFV-Cys), 2-(chlorofluoromethyl)benzimidazole and 2-mercaptoquinoxaline were also found as OPD adducts. However, with CDFV-Cys the ratio of 2-(chlorofluoromethyl) benzimidazole to 2-mercaptoquinoxaline was 12-fold higher than in the case of CTFE-Cys. These results suggest an important second mechanism of formation of 2-mercaptoquinoxaline with CTFE-Cys. The formation of 2-mercaptoquinoxaline could also be explained by reaction of OPD with 2,3,3-trifluorothiirane as a second reactive intermediate for CTFE-Cys. Comparable results were obtained when comparing OPD adducts from DCDFE-Cys and TCV-Cys. Both DCDFE-Cys and TCV-Cys form dichlorothionoacylating species. However, DCDFE-Cys forms 21-fold more 2-mercaptoquinoxaline than TCV-Cys, which may be explained by its capacity to form 3-chloro-2,2-difluorothiirane next to dichlorothionoacyl fluoride. In order to explain the apparent differences in the preference of thiols to form different reactive intermediates, free enthalpies of formation (delta 1G) of thiolate anions and their possible rearrangement products, thionoacyl fluorides and thiiranes, derived from TFE-Cys, CTFE-Cys, and DCDFE-Cys, were calculated by ab initio calculations. For TFE-thiolate, formation of difluorothionoacetyl fluoride is energetically favored over formation of the thiirane. In contrast, the thiirane pathway is favored over the thionoacyl fluoride pathway for CTFE- and DCDFE...

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Section: Introductionmentioning

confidence: 99%

Bioactivation of S-(2,2-Dihalo-1,1-difluoroethyl)-l- cysteines and S-(Trihalovinyl)-l-cysteines by Cysteine S-Conjugate β-Lyase: Indications for Formation of both Thionoacylating Species and Thiiranes as Reactive Intermediates

Commandeur¹,

King²,

Koymans³

et al. 1996

Chem. Res. Toxicol.

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“…Derr and Schultze (28) first described the binding of cysteine conjugate metabolites to biological macromolecules. Further work by this group clearly demonstrated the enzymatic cleavage of DCVC by a PLPlike enzyme and the elimination of a reactive thiol containing species as a 0-elimination product (29). The enzyme was later named cysteine conjugate 0-lyase and has been purified from a variety of sources (22,30).…”

Section: Discussionmentioning

confidence: 99%

Formation, characterization, and immunoreactivity of lysine thioamide adducts from fluorinated nephrotoxic cysteine conjugates in vitro and in vivo

Fisher

Hayden²,

Bruschi³

et al. 1993

Chem. Res. Toxicol.

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Fluorinated nephrotoxic cysteine conjugates undergo bioactivation via the beta-lyase pathway to thionoacetyl fluorides (TAF), the putative reactive intermediates. The TAF derived from S-(1,1,2,2,-tetrafluoroethyl)-L-cysteine (TFEC) difluorothionoacetylates amine nucleophiles found in proteins and lipids. A specific antisera, raised against (trifluoroacetamido)lysine adducts formed in vivo after halothane treatment, has previously been used to localize TFEC-derived protein adducts immunohistochemically, and a good correlation between adduction and toxicity was demonstrated. Interestingly, thioamide formation is facilitated by acyl-transfer catalysts such as imidazoles and phenols. However, although putative lysine adducts have been reported to be formed from the related TAF derived from S-(2-chloro-1,1,2-trifluoroethyl)-L-cysteine (CTFC), protein adducts derived from CTFC metabolism have not been completely characterized. In the present investigation we characterize (chlorofluorothionacetamido)lysine (CFTAL) adduct formation during S-(2-chloro-1,1,2-trifluoroethyl)-L-cysteine (CTFC) metabolism, both in vitro and in vivo. Our data indicate that formation of CTFC-derived lysine thioamides was not as dependent on nucleophilic catalysis as observed for TFEC, and this appears to be due to an apparent greater reactivity of the TAF resulting in a higher trapping efficiency in the absence of catalyst. Also, qualitative and quantitative differences in the structures and time course of CTFC versus TFEC adduct breakdown were observed. Antibodies raised against the halothane metabolite protein adduct (trifluoroacetamido)lysine cross-react with specific mitochondrial proteins from the kidneys of TFEC-treated rats. Using this antibody, we have found that the pattern of adducted proteins from TFEC- and CTFC-treated Fischer rats was similar, but the intensity was considerably lower after treatment with equimolar concentrations of CTFC in vivo.

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Regulation of a S(trans‐1,2‐dichlorovinyl)‐L‐cysteine‐induced renal tubular toxicity by glutathione

Hassall

Brendel

Gandolfi

1983

J of Applied Toxicology

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The nephrotoxin S-(1,2-dichlorovinyl)-L-cysteine (DCVC) is cleaved in the renal tubules to produce a reactive electrophilic intermediate. If this intermediate is responsible for the toxicity, addition of the nucleophilic scavenger glutathione (GSH) should decrease toxicity, and depletion of tubular GSH should enhance toxicity. GSH was added to isolated rabbit renal tubules simultaneously with, 15 min before, and 15 min after the addition of DCVC. The active accumulation of the organic anion para-aminohippuric acid (PAH) and organic cation tetraethylammonium bromide (TEA) was used as an index of renal toxicity. Incubation of renal tubules with 0.01-1 mM DCVC for 15 min decreased active transport, with complete inhibition at 1 mM. This was accompanied by a 50% decrease in non-protein sulfhydryl concentration. The addition of GSH (6 mM) simultaneously with DCVC completely prevented any decrease in active transport. The addition of GSH (6 mM) to tubules in which active transport was inhibited by DCVC reversed the inhibition to 80% of control. Similar enhancement of active transport occurred when tubules isolated 1 h after in vivo exposure to DCVC at 20-100 mg kg-1 were incubated with GSH (6 mM). Preincubation of renal tubules with GSH (5-15 mM) made them more refractory to the DCVC-induced decreased PAH and TEA transport. The inhibition of active transport by DCVC is enhanced if the tubular non-protein sulfhydryl is first lowered by diethyl maleate or glycidol. Thus, the tubular GSH concentration appears to be an integral component in regulating the alterations in active transport caused by DCVC.

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Interaction of S-(1,2-dichlorovinyl)-l-cysteine with proteins

Cited by 25 publications

References 20 publications

Bioactivation of S-(2,2-Dihalo-1,1-difluoroethyl)-l- cysteines and S-(Trihalovinyl)-l-cysteines by Cysteine S-Conjugate β-Lyase: Indications for Formation of both Thionoacylating Species and Thiiranes as Reactive Intermediates

Bioactivation of S-(2,2-Dihalo-1,1-difluoroethyl)-l- cysteines and S-(Trihalovinyl)-l-cysteines by Cysteine S-Conjugate β-Lyase: Indications for Formation of both Thionoacylating Species and Thiiranes as Reactive Intermediates

Formation, characterization, and immunoreactivity of lysine thioamide adducts from fluorinated nephrotoxic cysteine conjugates in vitro and in vivo

Regulation of a S(trans‐1,2‐dichlorovinyl)‐L‐cysteine‐induced renal tubular toxicity by glutathione

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