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Spectrophotometric Screening for Potential Inhibitors of Cytosolic Glutathione S-Transferases

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Published on: October 10, 2020

Glutathione-dependent bioactivation.

Lawrence H Lash¹

¹Wayne State University School of Medicine, Detroit, Michigan, USA.

Current Protocols in Toxicology

|October 10, 2012

Summary

This summary is machine-generated.

The glutathione (GSH) conjugation pathway can detoxify or bioactivate substrates. Certain cysteine conjugates, rather than being excreted, form reactive intermediates in the kidneys, leading to toxicity.

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Area of Science:

Biochemistry
Toxicology
Drug Metabolism

Background:

The glutathione (GSH) conjugation pathway typically detoxifies electrophilic substrates via GSH S-transferase (GST) enzymes.
This process usually results in polar mercapturates readily excreted in urine.

Purpose of the Study:

To explore the bioactivation of specific GST substrates.
To understand the mechanisms underlying nephrotoxicity and chemotherapeutic prodrug activation.

Main Methods:

Analysis of the glutathione conjugation pathway.
Investigation of enzyme kinetics and substrate metabolism.
Identification of reactive intermediates.

Main Results:

Some GST substrates are bioactivated instead of detoxified.
Cysteine S-conjugates act as crucial branch points in this pathway.
Bioactivated cysteine S-conjugates are metabolized in the kidneys to reactive intermediates.

Conclusions:

The classical view of GSH conjugation as solely detoxification is incomplete.
Kidney metabolism of specific cysteine conjugates can lead to toxicity or prodrug activation.
Understanding these pathways is critical for predicting halogenated solvent nephrotoxicity and designing chemotherapeutics.