Contemporary issues in toxicology

Glutathione conjugate mediated toxicities

Terrence Monks, M. W. Anders, W. Dekant, J. L. Stevens, Serrine Lau, P. J. Van Bladeren

Research output: Contribution to journalArticle

Abstract

Glutathione (γ-glutamyl-L-cysteinylglycine; GSH) is present in high concentrations in most living cells and participates in a variety of vital cellular reactions. In particular, GSH protects cells from potentially toxic electrophiles formed via the metabolism of xenobiotics, and such reactions have long been associated with the process of detoxication (Baumann and Preusse, 1879; Jaffe, 1879). Compounds that form GSH conjugates are processed by γ-glutamyl transpeptidase (γ-GT) and dipeptidases to cysteine S-conjugates, which are usually excreted in urine as their corresponding mercapturic acids (S-substituted N-acetyl-L-cysteine conjugates). In addition, GSH peroxidase activity, whether catalyzed by the selenium-dependent GSH peroxidase or by the GSH S-transferases, serves to detoxify hydrogen peroxide and organic hydroperoxides. However, in recent years, evidence indicating that GSH conjugation plays an important role in the formation of toxic metabolites from a variety of chemicals has accumulated. Thus, several classes of compounds are converted, via conjugation with GSH, into either cytotoxic, genotoxic, or mutagenic metabolites. The purposes of the symposium on 'Glutathione Conjugate Mediated Toxicities' presented at the 1990 Society of Toxicology Annual Meeting were to discuss recent findings in this rapidly moving field, to present ideas on the mechanisms and modulation of GSH conjugate-dependent toxicities, to present a consensus on the broader significance of this work, and to identify directions for future research. This paper summarizes these presentations. GSH conjugation reactions are involved in the bioactivation of several classes of xenobiotics, and four types of GSH-dependent bioactivation reactions can be identified: (1) directly toxic GSH conjugates may be formed from vicinal dihaloalkanes via formation of electrophilic sulfur mustards; (2) cysteine conjugate β-lyase-dependent bioactivation is involved in the selective nephrotoxicity of haloalkenes; (3) GSH conjugates of hydroquinones and isothiocyanates may serve as transport and targeting metabolites; and (4) GSH-dependent reactions may be involved in the release of toxic agents from precursor organic thiocyanates and nitrosoguanidines (N-methyl-N'-nitro-N-nitrosguanidine).

Original languageEnglish (US)
Pages (from-to)1-19
Number of pages19
JournalToxicology and Applied Pharmacology
Volume106
Issue number1
DOIs
StatePublished - 1990
Externally publishedYes

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Poisons
Toxicology
Glutathione
Toxicity
Metabolites
Acetylcysteine
Xenobiotics
Hydrogen Peroxide
Peroxidase
cysteinylglycine
Cysteine
Dipeptidases
Thiocyanates
Mustard Gas
Hydroquinones
Isothiocyanates
Methylnitronitrosoguanidine
Lyases
gamma-Glutamyltransferase
Selenium

ASJC Scopus subject areas

  • Pharmacology
  • Toxicology

Cite this

Contemporary issues in toxicology : Glutathione conjugate mediated toxicities. / Monks, Terrence; Anders, M. W.; Dekant, W.; Stevens, J. L.; Lau, Serrine; Van Bladeren, P. J.

In: Toxicology and Applied Pharmacology, Vol. 106, No. 1, 1990, p. 1-19.

Research output: Contribution to journalArticle

Monks, Terrence ; Anders, M. W. ; Dekant, W. ; Stevens, J. L. ; Lau, Serrine ; Van Bladeren, P. J. / Contemporary issues in toxicology : Glutathione conjugate mediated toxicities. In: Toxicology and Applied Pharmacology. 1990 ; Vol. 106, No. 1. pp. 1-19.
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AU - Van Bladeren, P. J.

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