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

Abstract

The concept that reactive intermediate formation during the biotransformation of drugs and chemicals is an important bioactivation mechanism was proposed in the 1970s and is now accepted as a major mechanism for xenobiotic-induced toxicity. The enzymology of reactive intermediate formation as well as the characterization of the formation and fate of reactive intermediates are now well-established. The mechanism by which reactive intermediates cause cell damage and death is, however, still poorly understood. Although most xenobiotic-metabolizing enzymes catalyze the bioactivation of chemicals, glutathione-dependent biotransformation has been largely associated with detoxication processes, particularly mercapturic acid formation. Abundant evidence now shows that glutathione-dependent biotransformation constitutes an important bioactivation mechanism for halogen-containing drugs and chemicals and has for many compounds been implicated in their organ-selective toxicity and in their mutagenic and carcinogenic potential. The glutathione-dependent biotransformation of haloalkenes is the first step in the cysteine S-conjugate beta-lyase pathway for the bioactivation of nephrotoxic haloalkenes. This pathway has been a rich source of reactive intermediates, including thioacyl halides, alpha-chloroalkenethiolates, 3-halo-alpha-thiolactones, 2,2,3-trihalothiiranes, halothioketenes, and vinylic sulfoxides. Glutathione-dependent bioactivation of gem-dihalomethanes and 1,2-, 1,3-, and 1,4-dihaloalkanes leads to the formation of alpha-chlorosulfides, thiiranium ions, sulfenate esters, and tetrahydrothiophenium ions, respectively, and these reactions lead to reactive intermediate formation.

Role of Glutamine Transaminases in Nitrogen, Sulfur, Selenium, and 1-Carbon Metabolism

“…For reviews see refs. [36][37][38][39]. (1) is converted to pyruvate (2), ammonium and a sulfurcontaining fragment that has the theoretical structure 1,2-dichloroethylenethiol (3).…”

Bacillithiol, a New Player in Bacterial Redox Homeostasis

“…As a result of these facile reactions, mercapturic acids (N-acetylcysteine-S-conjugates) of xenobiotics can be monitored in the urine of patients. Bioconjugation reactions with GSH contribute significantly to the toxicity of some xenobiotics, such as halogen-containing drugs (2).…”

Trichloroethylene and trichloroethanol-induced formic aciduria and renal injury in male F-344 rats following 12 weeks exposure

“…Conjugation of TCE-OH occurs primarily in the liver and hence it is difficult to know exactly how much free TCE-OH the kidney receives, we therefore selected a dose that produced a similar extent of formic aciduria as TCE. The current view is that conjugation of TCE via GSH is responsible for the renal injury, due to the formation of DCVC or its sulphoxide (Anders 2008;Green et al, 1997;Lash et al, 1994). In contrast, the production of formic aciduria following TCE or TCE-OH has also been proposed as a possible mechanism for causing long term renal injury (Green et al, 1998;2003).…”

“…This occurs following glutathione conjugation of TCE by glutathione Stransferases, followed by further metabolism by enzymes of the mercapturic acid pathway to form S-1,2-(dichlorovinyl)-L-cysteine (DCVC) which accumulates in proximal renal tubule cells. DCVC is then cleaved by the enzyme cysteine conjugate β-lyase to produce a reactive thioketene (se Anders, 2008). This causes marked toxicity to the proximal renal tubules in rats and mice administered DCVC (Gandolfi et al, 1981;Darnerud et al, 1988;Vaidya et al, 2003;Green et al, 1997).…”