Glutathione S-transferases - A review

The Glutathione S-transferases (GSTs) form a group of multi-gene isoenzymes involved in the cellular detoxification of both xenobiotic and endobiotic compounds. GSTs have been divided into a number of subclasses, alpha (a), m u (mu), Pi (pi), and theta (theta). The classification was made on the basi s of sequence similarity and immunological cross-reactivity. GSTs show a hi gh level of specificity toward GSH but the electrophilic second substrate c an vary significantly both between and within the Glasses in spite of their sequence similarity. X-ray crystallography and site-directed mutagenesis studies have together e lucidated the structure and mechanism of GSTs. Catalysis occurs by conjugat ion with glutathione (GSH) and the less toxic and more hydrophilic products can then be partially metabolised and excreted. This invaluable service is however disadvantageous during chemotherapy where GSTs have been associate d with multi-drug resistance of tumour cells. Levels of expression of diffe rent isoforms of GSTs are tissue specific. The variations in expression bet ween normal and tumour cells are of interest and in most cases the levels o f GSTs are increased, especially pi-GST. Understanding the complex role tha t GSTs play in drug resistance begins with determining the pattern of isofo rm expression and the substrate specificities of each isoform. The use of i sozyme-specific, GSH analogues as inhibitors to modulate GST activity durin g chemotherapy is a promising strategy in the battle against cancer. This review attempts to provide a detailed overview of the literature conce rning the different classes of GSTs, their function and mechanism and the u se of GSTs as therapeutic targets for disease as current at the time of sub mission.