Glutathione S-transferase and glutathione peroxidase expression in normal and tumour human tissues

Abstract

Glutathione S-transferases play a central role in drug detoxification and have been implicated in the sensitivity of tumour cells to anticancer drugs. In this study, glutathione S-transferase (GST) isozyme expression in normal and tumour tissue from human lung, colon, stomach, breast, kidney and liver tissue has been quantified using sensitive and subunit specific radioimmunoassays (RIA), together with Western blot analysis and measurement of substrate metabolism. Glutathione S-transferase pi was the predominant GST in the majority of the tumours examined. The concentration of this enzyme was increased significantly in tumour tissue relative to normal lung, colon, and stomach tissue. A strong correlation was observed (r = 0.77, P less than 0.01) between GST activity and GST pi levels in those tumour samples. The concentrations of the alpha class GST, the predominant isoenzymes in normal stomach, kidney and liver, decreased dramatically in tumour tissue from these organs. Western blot analysis revealed the presence of novel polypeptides that cross-reacted with antisera raised against alpha and mu class GST. Our data demonstrates that although GST pi is the predominant GST isoenzyme in many tumours, significant levels of the other GST subunits are also present and collectively can represent a significant proportion of the GST content. Therefore the properties of all the GST isoenzymes need consideration when assessing the role of these proteins in drug resistance. Selenium-dependent glutathione peroxidase, an enzyme activity also implicated in the mode of action of certain antitumour agents, was also studied and shown to be the predominant glutathione-dependent peroxidase in all tumours except the hepatoma.

Evaluation of glutathione S-transferase Pi in non-invasive ductal carcinoma of breast

“…The present study of a large number of patients has demonstrated loss of GST P expression in DCIS when compared with normal breast epithelium. These results differ from those in other epithelia in which GST P expression is increased in dysplasia and in carcinoma compared with normal cells (Sato, 1989;Howie et al, 1990). …”

“…cervical viral warts (Carder et al, 1990). A wide variety of invasive carcinomas show increased GSTP expression (Howie et al, 1990), although this is not a universal phenomenon (Harrison, 1993).GST P is the major GST class in breast cancers and it is overexpressed in a subclass of oestrogen receptor-poor carcinomas (Howie et al, 1989). The implications for therapy are highlighted by data from a breast carcinoma cell line showing that increased GST expression and loss of oestrogen receptors occurs during acquisition of a multidrug-resistant phenotype (Moscow et al, 1988;Vickers et al, 1988).…”

“…cervical viral warts (Carder et al, 1990). A wide variety of invasive carcinomas show increased GSTP expression (Howie et al, 1990), although this is not a universal phenomenon (Harrison, 1993).…”

Glutathione S-transferase expression in the human testis and testicular germ cell neoplasia

“…The GSTs comprise at least five gene families represented by the four cytosolic classes, Alpha, Mu, Theta and Pi, and at least one distinct membrane-associated microsomal class (Morgenstern et al, 1990). The distribution of GST isoenzymes in human tissues is not uniform and altered expression of GSTs has been demonstrated in a variety of tumour tissues (Howie et al, 1990). GST Pi acts as a marker of preneoplasia in animal models (Sato et al, 1987) and has been implicated in the acquisition of a drug resistant phenotype during carcinogenesis (Batist et al, 1986).…”

GSTA1 (glutathione S-transferase alpha 1)

“…Regarding GSH-dependent ∆ 5 -∆ 4 isomerase activity of this class of enzyme, it has been shown that steroidogenic factor 1 (SF-1) is involved in regulation of expression of GSTA genes (Matsumura et al, 2013). Aberrant overexpression has been observed in various malignancies such as colorectal (Hengstler et al, 1998) and lung cancer (Carmichael et al, 1988), while decrease in alpha class GSTs has been observed in stomach and liver tumors (Howie et al, 1990). A detailed recent review on GSTA1 can be found in Wu and Dong, 2012.…”