The role of glutathione and glutathione transferases in chemical carcinogenesis.

Published on Jan 1, 1990in Critical Reviews in Biochemistry and Molecular Biology6.069
· DOI :10.3109/10409239009090605
Brian F. Coles25
Estimated H-index: 25
(NCTR: National Center for Toxicological Research),
Brian Ketterer1
Estimated H-index: 1
(NCTR: National Center for Toxicological Research)
The importance of the covalent binding of electrophilic metabolites of carcinogens to macromolecules, in particular DNA, as a critical event in chemical carcinogenesis was established in the 1960s. This was largely through the work of James and Elizabeth Miller and colleagues.' Since then, the metabolism of many chemical carcinogens has been investigated and the details of their activation to electrophilic metabolites have been established. That glutathione (GSH) can act as an alternative (competing) nucleophilic site to the nucleophilic portions of DNA, and hence afford protection against genotoxic electrophiles, was first recognized by Boyland and Chasseaud4 and Chassea~d.~ It has now been established that GSH reacts with a number of electrophiles derived from carcinogens and that these reactions form an important detoxification me~hanism.~.~ Boyland's laboratory was also the first to show that many of the reactions of GSH with electrophiles are enzyme catalysed.' This catalysis was referred to as glutathione S-transferase (GSH transferase) activity, and was shown to reside in a number of isoenzymes with broad substrate specificity by Jakoby and colleagues.* It is now known that these isoenzymes (E.C. are products of a gene superfamily?-'* In this review the role of GSH conjugation in the overall metabolism of carcinogens is discussed both in general and in relation to specific carcinogens.
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