Cysteine, dichlorovinyl

Although trichloroethylene itself may not be genotoxic, several of its metabolites are reactive and potentially genotoxic compounds (Miller and Guengerich 1982). Several isomers of 1,2-dichlorovinyl-cysteine, a product of trichloroethylene metabolism in the kidney, are mutagenic in the in vitro Ames assay... 

Bimer G, Vamvakas S, Dekant W, et al. 1993. Nephrotoxic and genotoxic N-acetyl-S-dichlorovinyl-L-cysteine is a urinary metabolite after occupational 1,1,2-trichloroethene exposure in humans Implications for the risk of trichloroethene exposure. Environ Health Perspect 99 281-284. 

Commandeur JNM, Vermeulen NPE. 1990a. Identification of N-acetyl-S-(2,2-dichlorovinyl) and N-acetyl-S-(l,2-dichlorovinyl)-L-cysteine as two regioisomeric mercapturic acids of trichloroethylene in the rat. Chem Res Toxicol 3 212-218. 

Dekant W, Metzler M, Henschler D. 1986a. Identification of S-l,2-dichlorovinyl- N-acetyl-cysteine as a urinary metabolite of trichloroethylene A possible explanation for its nephrocarcinogenicity in male rats. Biochem Pharmacol 35 2455-2458. 

Eyre RJ, Stevens DK, Parker JC, et al. 1995b. Renal activation of trichloroethene and S -(l,2-dichlorovinyl)-L-cysteine and cell proliferative responses in the kidneys of F344 rats and B6C3F, mice. J Toxicol Environ Health 46 465-481. 

McKinney LL, Weakley FB, Eldridge AC, et al. 1957. S-(dichlorovinyl)-L-cysteine an agent causing fatal aplastic anemia in calves. J Am Chem Soc 79 3932-3933. 

Anderson PM, Schultze MO. Cleavage of S-(l,2-dichlorovinyl)-L-cysteine by an enzyme of bovine origin. Arch Biochem Biophys 1965 lll(3) 593-602. 

Hassall, C.D., Gandolfi, A.J. and Brendel, K. (1983). Correlation of the in vivo and in vitro renal toxicity of S-(1.2-dichlorovinyl)-L-cysteine. Drug. Chem. Toxicol. 6 507-520. 

Zhang, G. and Stevens, J.L. (1989). Tansport and activation of 5-(l, 2-dichlorovinyl)-L-cysteine andA-acetyl-S-(l,2-dichlorovinyl)-L-cysteine in rat kidney proximal tubules. Toxicol. Appl. Pharmacol. 100 51-61. 

These subsequent metabolic transformations are known to be involved in the nephrotoxicity of a number of compounds such as S-(l,2-dichlorovinyl)-L cysteine and hexachlorobu-tadiene (see chap. 7). Thus, although the initial glutathione conjugation may be a detoxication step, the final product of this phase 3 reaction may prove to be toxic. 

Trichloroethylene is metabolized similarly and gives rise to dichlorovinyl cysteine. It has been found that S-(l,2-dichlorovinyl)-L-cysteine (DCVC) and S-(2-chloroethyl)-DL-cysteine (CEC) (Fig. 7.30) are both nephrotoxic when administered to animals causing renal proximal tubular necrosis. CEC does not require 3-lyase activation to be nephrotoxic, but can rearrange, possibly to a reactive episulfonium ion, by nucleophilic displacement of the chlorine atom. These compounds decrease the activity of the renal tubular anion and cation transport system. 

Figure 7.30 The structures of S-(1,2-dichlorovinyl)-L-cysteine and S-(2-chloroethyl)-DL-cysteine.

Dekant, W., Berthold, K., Vamavkas, S., Henschler, D. Anders, M.W. (1988) Thioacylating intermediates as metabolites of S-(l, 2-dichlorovinyl)-L-cysteine and 6 -(l,2,2-trichlorovinyl)-L-cysteine formed by cysteine conjugate P-lyase. Chem. Res. Toxicol., 1, 175-178... 

Patel, N., Bimer, G, Dekant, W. Anders, M.W. (1994) Glutathione-dependent biosynthesis and bioactivation of, S -(l,2-dichlorovinyl)glutathionc and. S -(1,2-dichlorovinyl)-i,-cysteine, the glutathione and cysteine S-conjugates of dichloroacetylene, in rat tissues and subcellular fractions. Drug Metab. Dispos., 22, 143-147... 

Vamvakas, S., Bittner, D., Dekant, W. Anders, M.W. (1992) Events that precede and that follow S-(l,2-dichlorovinyl)-L-cysteine-induced release of mitochondrial Ca2+ and their association with cytotoxicity to renal cells. Biochem. Pharmacol., 44, 1131-1138... 

Cysteine 5-conjugate P-lyase activity has been implicated in the bioactivation of certain halogenated alkenes. This bioactivation results from the generation of reactive thiols. The thiol produced by the P-lyase-dependent metabolism of 5(1,2-dichlorovinyl)-L-cysteine is an unstable electrophile that binds covalently to cellular macromolecules and leads to nephrotoxicity and genotoxicity. Alternatively, certain... 

Incubation mixtures contained 75 pL of substrate solution (in 50 mM Tris-HC1 buffer, pH 8.6) and enzyme solution in the same buffer to give a final volume of 300 pL. Good substrates included 5-1,2-dichlorovinyl-L-cysteine used at a concentration of 1 mM. After an incubation at 37°C for 10 minutes, the incubations were terminated by adding 1.0 mL of 12 mM o-phenylenedia-mine in 3 M HC1. The caps of the incubation vials were closed and pierced with a needle before being placed in a preheated oven at 60°C for 60 minutes. The samples were centrifuged, and 100 pL of the supernate was analyzed by HPLC. 

Cytolysis The phenomenon where the cell undergoes destruction, particularly due to the disintegration of cell membrane DART Developmental and reproductive toxicology DBCP l,2-dibromo-3-chloropropane DCVC 5-(l,2-dichlorovinyl)-L-cysteine... 

As for stereoselectivity, relatively little is known as yet, except that the natural R configuration in the cysteine residue is a prerequisite for a cysteine conjugate to be a substrate of p-lyase. This fact has been used as a tool to ascertain the role of p-lyase in the development of nephrotoxicity by cysteine conjugates. No data are presently available with regard to the substrate-stereoselective effects of the noncysteine part of the thioether substrates of p-lyase (Commandeur and Vermeulen, 1990). Such stereoselective effects may be anticipated, however, since, for example, the regioisomeric 1,2- and 2,2-dichlorovinyl-LrCysteine conjugates have also... 

Wolfgang GH, Gandolfi AJ, Stevens JL, and Brendel K. N-acetyl S-(l,2-dichlorovinyl)-L-cysteine produces a similar toxicity to S-(l,2-dichlorovinyl)-L-cysteinein rabbit renal slices differential transport and metabolism. Toxicology and Applied Pharmacology 101 205-219,1989. 

Lash LH, Hueni SE, Putt DA. Apoptosis, necrosis, and cell proliferation induced by S-(1,2-dichlorovinyl)-L-cysteine in primary cultures of human proximal tubular cells.Toxicology and Applied Pharmacology 177 1-16, 2001. 

S-(l,2-Dichlorovinyl)-L-cysteine (DCVC) is a model nephrotoxicant and cataractogen used to induce acute renal failure and cataracts in experimental animals to study the biochemical, physiological, and molecular mechanisms underlying the disease. 

Figure 1 Metabolism of DCVC and mechanism of nephrotoxicity. O S-, 2-dichlorovinyl)-L-cysteine S-(1,2-dichlorovinyl)-A/-acetyl-L-cysteine the a-keto acid metabolite of S-(1,2-dichlorovinyl)-L-cysteine O S-(1,2-dichlorovinyl)-L-cysteine sulfoxide 1,2-dichlorovin-ylthiol S-[1-chloro-2-(S-glutathionyl)vinyl]-L-cysteine sulfoxide.

S-(1,2-Dichlorovinyl)-L-Cysteine, Pages 747-749, Vishal S. Vaidya and Harihara M. Mehendale SummaryPlus Full Text + Links PDF (82 K)... 

Ripp SE, Overby EIT, Phllpot RM, Elfarra AA. Oxidation of cysteine S-conjugates by rabbit liver microsomes and cDNA-expressed flavin-containing mono-oxygenases studies with S-(l,2-dichlorovinyl)-E-cysteine, S-(l,2,2 trichlorovinyl)-Ecysteine, S-allyl-E-cysteine, and S-benzyl-L-cysteine. Mol Pharmacol 1997 51 507-515. 

Cummings BS, Lash LH. Metabolism and toxicity of trichloroethylene and S-(l,2-dichlorovinyl)-L-cysteine in freshly isolated human proximal tubular cells. Toxicol Sci 2000 53 458-466. 

Responses of primary cultures of hPT cells to the nephrotoxic metabolite of TCE 5-(l,2-dichlorovinyl)-L-cysteine (DCVC) provide an illustration of this principle. We showed that primary cultures of hPT cells incubated with DCVC undergo necrotic cell death at relatively high concentrations (>100 pM) and long incubation times (>24h), whereas incubation with relatively low concentrations (<100 pM) for relatively short periods of time ( 8h) can result in apoptosis (Lash et al., 2(X)1). An increase in the proportion of hPT cells in S-phase (as assessed by flow cytometry) and rates of DNA synthesis (as assessed by incorporation of [ H]-dTTP) also occurred with DCVC treatment and followed similar patterns as apoptosis. This suggests that such low-dose, early responses can only occur when the hPT cell population still has adequate energy and viability. 

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