PI-CLASS GLUTATHIONE-S-TRANSFERASE - REGULATION AND FUNCTION

Our laboratory has been involved in the study of Glutathione S-transfe rase pi (GST pi) for many years, both in terms of regulation of gene e xpression and in trying to understand the endogenous function(s) of th is enzyme and also what role it may play in the carcinogenic process [ 1]. Over-expression of GST pi has been associated with carcinogenesis and the development of many different human tumours, for example testi s [2], ovarian [3] and colorectal [4] and is often inversely correlate d with prognosis or patient survival [5,6]. In addition, GST Pi has be en implicated in the acquisition of antineoplastic drug resistance [7- 9]. In order to study the transcriptional regulation of this gene, we have utilised a multi-drug resistant derivative (VCREMS) of the human mammary carcinoma cell line, MCF7, in which GST P1 mRNA and protein ar e significantly elevated in the absence of gene amplification [10-13]. Interestingly, we have recently reported the discovery of polymorphis ms at the GSTP1 locus, resulting in two alleles GSTP1a and GSTP1b. In the study, the GSTP1b allele was found with increased frequency in bla dder and testicular cancer, while the GSTP1a allele was significantly decreased in cases of prostate cancer [14]. In an attempt to elucidate the endogenous role(s) of GST pi, we have used homologous recombinati on in embryonic stem (ES) cells to inactivate both murine GST Pi genes and create a mouse strain completely deficient in the expression of t his enzyme. This provides us with a unique animal model with which to study the effects of the absence of GST pi expression on the metabolis m and pharmacokinetics of xenobiotics. (C) 1998 Elsevier Science Irela nd Ltd. All rights reserved.