Glutathione S-transferase isoenzymes in human tumours and tumour derived cell lines

Abstract

Edinburgh, Edinburgh Royal Infirmary, Edinburgh EH3 9 YW; and 3Department of Clinical Oncology, Newcastle General Hospital, Newcastle-upon-Tyne, UK.Summary An increasing body of evidence indicates that glutathione S-transferases play a role in the intrinsic and acquired resistance of tumours to anticancer drugs. In view of the wide use of tumour cell lines to understand the factors which confer either sensitivity or resistance to chemotherapeutic agents we have determined glutathione S-transferase (GST) activity and isozyme composition in nine human cell lines. These data have been compared with the values obtained in solid tumours. In most cases overall GST activity was higher in the tumours than in the cell lines. This was most pronounced for the breast tumour samples relative to MCF7 cell line. The pi class GST subunit was present at similar concentration in the cell lines and the tumours, and in most cases was the most abundant subunit present. The alpha and mu class GST were expressed in most of the cell lines but at much lower concentration than the pi class subunit. Also considerable variability particularly in the expression of the mu subunits was observed. This was also the case for the expression of these subunits in the solid tumour samples. The levels of these GSTs (when expressed) in the solid tumours was invariably higher than that observed in the cell lines. There are therefore several similarities but also some significant differences in GST expression in solid tumours and cell lines. Whether the differences are because expression is lost during the generation of the cell lines or whether it reflects the individuality of human tumours remains to be clearly established.The glutathione S-transferases (GST) are a multigene family of dimeric proteins which play a central role in the detoxification of electrophilic xenobiotics (Chasseaud, 1979). In man, cytosolic GSTs have been divided into three major classes termed alpha (basic), mu (neutral) and pi (acidic) (Mannervik, 1985;Stockman et al., 1987). Proteins within these groups have marked differences in their substrate specificity. There is a growing body of evidence which indicates that GST play an important role in both carcinogenesis and drug resistance. For example, certain compounds which inhibit chemical carcinogenesis are often inducers of the GST in the target tissue (Benson et al., 1978;Benson & Barretto, 1985). These proteins are also overexpressed in preneoplastic lesions (Kitahara et al., 1984;Pickett et al., 1984; Buchmann et al., 1985) and, in addition, have been demonstrated to be increased in both normal and tumour cells exposed to cytotoxic drugs (Adams et al., 1985;Wang & Tew, 1985;Carmichael et al., 1986;Batist et al., 1986;Evans et al., 1987;Robson et al., 1987;Wolf et al., 1987a;.It is likely that glutathione S-transferase levels and isoenzyme composition will play a role in both the intrinsic and acquired resistance to cancer chemotherapy (McGowan & Fox, 1986;Wolf et al., 1987b;Buller et al., 1987;Lewis et al., 1988a). Surpris...

Correlation between metabolic enzyme GSTP1 polymorphisms and susceptibility to lung cancer

“…A number of studies have reported the distribution of GSTP1 exon 5 polymorphisms in different populations (4,(10)(11)(12). The results of the present study indicated that the mutant G allele of the GSTP1 gene occurred at a frequency of 23.0% in a Chinese population, and that the A/A, A/G, and G/G genotypes of the GSTP1 gene occurred at frequencies of 56.6, 40.8 and 2.6%, respectively.…”

“…The frequencies of the GSTP1 exon 5 polymorphism genotypes and the mutant T allele in populations from different regions reported by relevant studies are listed in Table VII. As shown in Table VII, the mutant G allele is most frequently observed in African Americans (42%), and occurs least frequently in Chinese (23%); while the frequency has been found to be 33-36% in European Americans, British and other Caucasians, and 26% in a Japanese population (4,(10)(11)(12). Although these samples may not be truly representative of their respective race, these results at least suggest the difference in the distribution of GSTP1 alleles and genotypes among Chinese, African Americans and Europeans.…”

Natural Products Modulate the Multifactorial Multidrug Resistance of Cancer

“…Several resistant cell lines have been shown to overexpress GST [81]. GSTs are detoxification enzymes conjugated of glutathione to the electrophilic center of various drugs and resulting in excretion of polar molecules.…”

GST isoenzymes in matched normal and neoplastic breast tissue

“…Kelley et al [20] reported that the average level of GSTs was substantially elevated in the cancer tissues than the levels in normal breast tissue from the same patient. An increasing body of evidence indicates that GSTs play a role in the intrinsic and acquired resistance of tumors to anticancer drugs [21]. Consequently, the increased activity of the GSTs in the breast tumor may be associated with the developed resistance of the tumors against the anticancer drugs.…”