THE GLUTATHIONE-S-TRANSFERASE SUPERGENE FAMILY - REGULATION OF GST AND THE CONTRIBUTION OF THE ISOENZYMES TO CANCER CHEMOPROTECTION AND DRUG-RESISTANCE

The glutathione S-transferases (GST) represent a major group of detoxi fication enzymes. All eukaryotic species possess multiple cytosolic an d membrane-bound GST isoenzymes, each of which displays distinct catal ytic as well as noncatalytic binding properties: the cytosolic enzymes are encoded by at least five distantly related gene families (designa ted class alpha, mu, pi, sigma, and theta GST), whereas the membrane-b ound enzymes, microsomal GST and leukotriene C-4 synthetase, are encod ed by single genes and both have arisen separately from the soluble GS T. Evidence suggests that the level of expression of GST is a crucial factor in determining the sensitivity of cells to a broad spectrum of toxic chemicals. In this article the biochemical functions of GST are described to show how individual isoenzymes contribute to resistance t o carcinogens, antitumor drugs, environmental pollutants, and products of oxidative stress. A description of the mechanisms of transcription al and posttranscriptional regulation of GST isoenzymes is provided to allow identification of factors that may modulate resistance to speci fic noxious chemicals. The most abundant mammalian GST are the class a lpha, mu, and pi enzymes and their regulation has been studied in deta il. The biological control of these families is complex as they exhibi t sex-, age-, tissue-, species-, and turnor-specific patterns of expre ssion. In addition, GST are regulated by a structurally diverse range of xenobiotics and, to date,at least 100 chemicals have been identifie d that induce GST; a significant number of these chemical inducers occ ur naturally and, as they are found as nonnutrient components in veget ables and citrus fruits, it is apparent that humans are likely to be e xposed regularly to such compounds. Many inducers, but not all, effect transcriptional activation of GST genes through either the antioxidan t-responsive element (ARE), the xenobiotic-responsive element (XRE), t he GST P enhancer 1(GPE), or the glucocorticoid-responsive element (GR E). Barbiturates may transcriptionally activate GST through a Barbie b ox element. The involvement of the Ah-receptor, Maf, Nrl, Jun, Fos, an d NF-beta B in GST induction is discussed. Many of the compounds that induce GST are themselves substrates for these enzymes, or are metabol ized (by cytochrome P-450 monooxygenases) to compounds that can serve as GST substrates, suggesting that GST induction represents part of an adaptive response mechanism to chemical stress caused by electrophile s. It also appears probable that GST are regulated in vivo by reactive oxygen species (ROS), because not only are some of the most potent in ducers capable of generating free radicals by redox-cycling, but H2O2 has been shown to induce GST in plant and mammalian cells: induction o f GST by ROS would appear to represent an adaptive response as these e nzymes detoxify some of the toxic carbonyl-, peroxide-, and epoxide-co ntaining metabolites produced within the cell by oxidative stress. Cla ss alpha, mu, and pi GST isoenzymes are overexpressed in rat hepatic p reneoplastic nodules and the increased levels of these enzymes are bel ieved to contribute to the multidrug-resistant phenotype observed in t hese lesions. The majority of human tumors and human tumor cell lines express significant amounts of class pi GST. Cell lines selected in vi tro for resistance to anticancer drugs frequently overexpress class pi GST, although overexpression of class alpha and mu isoenzymes is also often observed. The mechanisms responsible for overexpression of GST include transcriptional activation, stabilization of either mRNA or pr otein, and gene amplification. In humans, marked interindividual diffe rences exist in the expression of class alpha, mu, and theta GST. The molecular basis for the variation in class alpha GST is not known. Abs ence of certain class mu and theta GST can be attributed to deletion o f the GSTM1 gene in 50% of the population and deletion of the GSTT1 ge ne in 16% of the population. The biological consequences of failure to express hGSTM1 or hGSTT1 protein can include susceptibility to bladde r, colon, skin, and possibly lung cancer.