Thioacylating intermediates as metabolites of S-(1,2-dichlorovinyl)-L-cysteine and S-(1,2,2-trichlorovinyl)-L-cysteine formed by cysteine conjugate .beta.-lyase

Abstract

The bioactivation mechanism of S-(1,2-dichlorovinyl)-L-cysteine (DCVC) and S-(1,2,2-trichlorovinyl)-L-cysteine (TCVC) was studied with cysteine conjugate beta-lyase (beta-lyase) from Salmonella typhimurium and with the pyridoxal phosphate model N-dodecylpyridoxal bromide (PL-Br) as catalysts and with GC/MS to identify the metabolites formed. PL-Br converted S-2-benzothiazolyl-L-cysteine to 2-mercaptobenzothiazole and S-benzyl-L-cysteine to benzyl mercaptan, demonstrating the ability of PL-Br to serve as a model for beta-lyase. PL-Br and bacterial beta-lyase converted DCVC to chloroacetic acid and chlorothionoacetic acid and TCVC to dichloroacetic acid. Incubations of PL-Br with the S-conjugates in the presence of diethylamine resulted in the formation of N,N-diethylchlorothioacetamide from DCVC and of N,N-diethyldichlorothioacetamide from TCVC. Attempts to trap the enethiols, which are the expected initial products formed by beta-elimination, by reaction with methyl iodide in incubations with the beta-lyase model were not successful. The formation of thioacylating agents from the enethiols may contribute to the cytotoxic and mutagenic effects of DCVC and TCVC.

S-(1,2,2-Trichlorovinyl)-l-cysteine Sulfoxide, a Reactive Metabolite ofS-(1,2,2-Trichlorovinyl)-l-cysteine Formed in Rat Liver and Kidney Microsomes, Is a Potent Nephrotoxicant

“…1) that readily loses chloride ion to form dichlorothioketene. Formation of dichlorothioketene has been implicated in TETRA-induced nephrotoxicity and nephrocarcinogenicity, because of its reactivity toward renal macromolecules (Dekant et al, 1988;Vamvakas et al, 1989a,b;Pä hler et al, 1999). In the second metabolic reaction, TCVC is oxidized by flavin-containing monooxygenases (FMOs) or cytochromes P450 to form S-(1,2,2-trichlorovinyl)-L-cysteine sulfoxide (TCVCS) (Ripp et al, 1997).…”

Carcinogenicity and Chronic Toxicity of 1,4-Dichloro-2-nitrobenzene in Rats and Mice by Two Years Feeding

“…Elfarra et al 40) demonstrated that intraperitoneal administration of S-(1,2-dichlorovinyl)glutathione and S-(1,2-dichlorovinyl)-L-cysteine to male F344 rats induced nephropathy, indicating a crucial role of the renal γ-glutamyltranspeptidase and cysteine conjugate β-lyase in the trichloroethylene-induced nephropathy. Dekant et al 41,42) reported that N-acetyl-S-(1,2-dichlorovinyl)-L-cysteine was identified as a urinary metabolite of trichloroethylene, and that thioacylating metabolites of S-(1,2-dichlorovinyl)-L-cysteine, which were formed by renal cysteine conjugate β-lyase, might contribute to the nephrotoxic and mutagenic effects. Our previous study 43) demonstrated that DCNB was metabolized and excreted into urine as N-acetyl-S-(4-chloro-3-nitrophenyl)-L-cysteine, suggesting that DCNB was metabolized to the glutathione conjugate in the liver, subsequently to S-(4-chloro-3-nitrophenyl)-L-cysteine in the kidney.…”

Development of a Physiologically-Based Pharmacokinetic Model of Trichloroethylene and Its Metabolites for Use in Risk Assessment

“…The bioactivation of DCVC to a reactive and mutagenic thioacylating intermediate is performed by cysteine conjugate I-lyase in the kidney (133). Although similar P-lyase activity has been measured in the kidney and liver, the two enzymes are distinct (134).…”