Glutathione S-transferase in hormonal carcinogenesis.
Treatment with testosterone propionate (TP) and diethylstilbestrol (DES) or TP and estradiol (E2) for 8-9 months causes development of leiomyosarcomas 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 detected 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 of a mu-class glutathione S-transferase (GST) (hGSTYBX). We have characterized this induction as a secondary response, i.e. requiring new protein synthesis. Here we describe homologies to known transcription factor-binding sites in the hGSTYBX promoter which may be involved in the induction event. hGSTYBX is a member of a superfamily of detoxification enzymes, induced by genotoxic compounds and reactive oxygen species (ROS). We also describe the effects of several known inducers of other GST family members on hGSTYBX. While implicated in many chemotherapeutic-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 treatment on GST levels in vivo, we have developed a polyclonal antibody to hGSTYBX, and conducted immunohistochemistry on tissues from control and treated animals. Treatment with TP and E2 causes a loss of hGSTYBX expression in the epithelium of the vas deferens. We hypothesize that the loss of this protective enzyme leaves the cells vulnerable to the genotoxic effects of estrogen or estrogenic metabolites.
Department of Microbiology and Immunology, Medical University of South Carolina, Charleston 29425-2230, USA.
C E
CE
Hudson
M M
MM
Kelly
D A
DA
Schwartz
D A
DA
Schofield
J E
JE
DeHaven
B A
BA
Schulte
J S
JS
Norris
D000818:Animals; D001483:Base Sequence; D001665:Binding Sites / Q000235:genetics; D006224:Cricetinae; D004273:DNA, Neoplasm / Q000235:genetics; D004054:Diethylstilbestrol / Q000633:toxicity; D004958:Estradiol / Q000633:toxicity; D015971:Gene Expression Regulation, Enzymologic; D005834:Genital Neoplasms, Male / Q000139:chemically induced* / Q000201:enzymology* / Q000235:genetics; D005982:Glutathione Transferase / Q000235:genetics / Q000378:metabolism*; D006728:Hormones / Q000633:toxicity*; D007890:Leiomyosarcoma / Q000139:chemically induced* / Q000201:enzymology* / Q000235:genetics; D008297:Male; D008647:Mesocricetus; D008969:Molecular Sequence Data; D011401:Promoter Regions, Genetic; D013739:Testosterone / Q000633:toxicity; D014407:Tumor Cells, Cultured; D014649:Vas Deferens
D004273:DNA, Neoplasm; D006728:Hormones; D013739:Testosterone; D004958:Estradiol; D004054:Diethylstilbestrol; D005982:Glutathione Transferase