GLUTATHIONE-S-TRANSFERASE IN HORMONAL CARCINOGENESIS

Treatment with testosterone propionate (TP) and diethylstilbestrol (DE S) or TP and estradiol (E2) for 8-9 months causes development of leiom yosarcomas in the vas deferens or uterus of Golden Syrian hamsters at a frequency of 100%. In males, treatment with estrogens alone results in renal tumors, fatal within 6 months. No leiomyosarcomas have been d etected after treatment with estrogens alone, perhaps due to this high mortality rate. In tissue culture, treatment with the glucocorticoid (GC) triamcinolone acetonide (TA) results in an increased expression o f a mu-class glutathione S-transferase (GST) (hGSTYBX). We have charac terized this induction as a secondary response, i.e. requiring new pro tein synthesis. Here we describe homologies to known transcription fac tor-binding sites in the hGSTYBX promoter which may be involved in the induction event. hGSTYBX is a member of a superfamily of detoxificati on enzymes, induced by genotoxic compounds and reactive oxygen species (ROS). We also describe the effects of several known inducers of othe r GST family members on hGSTYBX. While implicated in many chemotherape utic-resistant tumors, GST enzymes have not yet been characterized as a functional agent in hormonal carcinogenesis. This latter possibility is the focus of our investigations. To study the effects of hormone t reatment on GST levels in vivo, we have developed polyclonal antibody to hGSTYBX, and conducted immunohistochemistry on tissues from control and treated animals. Treatment with TP and E2 causes a loss of hGSTYB X expression in the epithelium of the vas deferens. We hypothesize tha t the loss of this protective enzyme leaves the cells vulnerable to th e genotoxic effects of estrogen or estrogenic metabolites. (C) 1998 El sevier Science Ireland Ltd. All rights reserved.