Role for an episulfonium ion in S-(2-chloroethyl)-DL-cysteine-induced cytotoxicity and its reaction with glutathione

Abstract

The cysteine S conjugate of 1,2-dichloroethane, S-(2-chloroethyl)-DL-cysteine (CEC), is hepatotoxic, nephrotoxic, and mutagenic. To determine the cellular and chemical mechanisms involved in CEC-induced toxicity and to assess the role of an episulfonium ion, the effect of CEC on the viability of isolated rat hepatocytes was studied. CEC addition resulted in both a time- and concentration-dependent loss of cell viability. Depletion of intracellular glutathione concentrations (greater than 70%) and inhibition of microsomal Ca2+ transport and Ca2+-ATPase activity preceded the loss of cell viability, and initiation of lipid peroxidation paralleled the loss of viability. The depletion of glutathione concentrations was partially attributable to a reaction between glutathione and CEC to form S-[2-(DL-cysteinyl)ethyl]glutathione, which was identified by NMR and mass spectrometry. N-Acetyl-L-cysteine, vitamin E, and N,N'-diphenyl-p-phenylenediamine protected against the loss of cell viability. N,N'-Diphenyl-p-phenylenediamine inhibited CEC-initiated lipid peroxidation but did not protect against cell death at 4 h, indicating that lipid peroxidation was not the cause of cell death. The analogues S-ethyl-L-cysteine, S-(3-chloropropyl)-DL-cysteine, and S-(2-hydroxyethyl)-L-cysteine, which cannot form an episulfonium ion, were not cytotoxic, thus demonstrating a role for an episulfonium ion in the cytotoxicity associated with exposure to CEC and, possibly, 1,2-dichloroethane. These results show that an alteration in Ca2+ homeostasis and the generation of an electrophilic intermediate may be involved in the mechanism of cell death.

Glutathione transferase in helminths

“…In plants the inhibitory actions of GSH conjugates of Tridiphane on plant GSH transferases have been exploited to act as synergist for the herbicide atrazine which is itself detoxified by GSH conjugation (Lamoureux & Rusness, 1986). Conjugation with GSH can also activate certain compounds as in the case of 1,2 dichloroethane (Webb et al 1987). The synthesis of toxic glutathione conjugates is a potential route for pro-drug design.…”

Unexpected increased thiabendazole tolerance in Haemonchus contortus resistant to anthelmintics by modulation of glutathione activity

“…The conjugates, if any, are toxic. Cases of increased toxicity after conjugation have been described for ethylene chloride (Barrett 1995), for hycanthone and oxamniquine in schistosomes (Cioli et al 1995), for dichloroethane in rat hepatocytes (Webb et al 1987), and for doxorubicin in tumor vertebrate cells (Asakura et al 1997a, b). Modulators indirectly reduced the amount of conjugates and, consequently, the toxicity as shown by Olas and Wachowicz (1998) for cisplatin toxicity to pig platelets after treatment with BSO.…”

Chemical Toxicology of Reactive Intermediates Formed by the Glutathione-Dependent Bioactivation of Halogen-Containing Compounds

“…Moreover, a role for glutathione and GSTs in the bioactivation of 1,2-dibromoethane was demonstrated (139,140). Other studies showed that S-(2-chloroethyl)-DL-cysteine, but not S-(3-chloropropyl)-DL-cysteine, S-ethyl-L-cysteine, S-(2-hydroxyethyl)-Nacetyl-DL-cysteine, or S-(2-hydroxyethyl)-DL-cysteine, is nephrotoxic in rats and cytotoxic in isolated rat hepatocytes (141,142).…”