Biosynthesis and Cellular Effects of Toxic Glutathione S-Conjugates

  • Wolfgang Dekant
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 387)

Abstract

Glutathione conjugation has been identified as an important detoxication reaction. However, several glutathione-dependent bioactivation reactions have been identified. Current knowledge on the mechanisms and the possible biological importance of these reactions is discussed in this article. Dichloromethane is metabolized by glutathione conjugation to formaldehyde via S-(chloromethyl)glutathione. Both compounds are reactive intermediates and may be responsible for the dichloromethane-induced tumorigenesis in sensitive species. Vicinal dihaloalkanes are transformed by glutathione S-transferase-catalyzed reactions to mutagenic and nephrotoxic S-(2-haloethyl)glutathione S-conjugates. Electrophilic episulphonium ions are the ultimate reactive intermediates formed and interact with nucleic acids. Several polychlorinated alkenes are bioactivated in a complex, glutathione-dependent pathway. The first step is hepatic glutathione S-conjugate formation followed by cleavage to the corresponding cysteine S-conjugates, and, after translocation to the kidney, metabolism by renal cystein conjugate β-lyase. β-Lyase-dependent metabolism of halovinyl cysteine S-conjugates yields electrophilic thioketenes, whose covalent binding to cellular macromolecules is likely responsible for the observed nephrotoxicity of the parent compounds. Finally, hepatic glutathione conjugate formation with hydroquinones and aminophenols yields conjugates that are directed to γ-glutamyltransferase-rich tissues, such as the kidney, where they undergo alkylation or redox cycling reactions, or both, that cause organ-selective damage.

Keywords

Flame Retardant Urinary Metabolite Glutathione Conjugation Mercapturic Acid Biliary Cannulation 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

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Copyright information

© Springer Science+Business Media New York 1996

Authors and Affiliations

  • Wolfgang Dekant
    • 1
  1. 1.Institut für Toxikologie und PharmakologieUniversität WürzburgWürzburgGermany

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