Glutathione‐Dependent Bioactivation

Lawrence H. Lash1

1 Wayne State University School of Medicine, Detroit, Michigan
Publication Name:  Current Protocols in Toxicology
Unit Number:  Unit 6.12
DOI:  10.1002/0471140856.tx0612s34
Online Posting Date:  November, 2007
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Abstract

The classical view of the glutathione (GSH) conjugation pathway involves GSH S‐transferase (GST)‐dependent formation of thioether conjugates between GSH and an electrophilic substrate, processing to yield the corresponding cysteine S‐conjugate, which is then converted to an N‐acetylcysteine conjugate (or mercapturate). Mercapturates of most GST substrates are rendered more polar and thus readily excreted in urine. In contrast, there is a growing number of GST substrates that, rather than being detoxified, are bioactivated. These substrates include several halogenated solvents, many of which are nephrotoxic because of the tissue distribution of GSH conjugation pathway enzymes and membrane transporters, and prodrugs of certain chemotherapeutic agents. Although the initiating steps are the same regardless of whether the substrate is detoxified or bioactivated, the cysteine conjugate functions as a branch point. Bioactivated cysteine S‐conjugates are metabolized in the kidneys by either cysteine conjugate β‐lyase or flavin‐containing monooxygenase to produce a reactive intermediate. Curr. Protoc. Toxicol. 34:6.12.1‐6.12.16. © 2007 by John Wiley & Sons, Inc.

Keywords: glutathione conjugation; glutathione S‐transferases; γ‐glutamyltransferase; cysteine conjugate β‐lyase; flavin‐containing monooxygenase; N‐acetyltransferase; acylase

     
 
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Table of Contents

  • Introduction
  • Overview of Enzymes Involved in GSH‐Dependent Bioactivation
  • Summary and Conclusions
  • Literature Cited
  • Figures
  • Tables
     
 
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Materials

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Literature Cited

Literature Cited
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