title: In vivo regulation of human glutathione transferase GSTP by chemopreventive agents.
abstract: Relatively little progress has been made in determining the in vivo regulation of glutathione S-transferase P (GSTP), particularly the human enzyme hGSTP1, despite being identified as a significant factor in carcinogenesis and development of drug resistance in tumor cell lines. Here, we report the characterization of a transgenic reporter mouse that reveals how hGSTP1 is regulated in vivo by chemopreventive agents. Basal expression was found in crypts and villi of the small and large intestine, bronchiolar epithelial cells, the epidermis and hair follicles, gall bladder epithelium, choroid plexus, and biliary epithelium. Expression was induced in different tissues by the antioxidant chemopreventive agents ethoxyquin and butylated hydroxyanisole. However, genetic deletion of the Nrf2 transcription factor, which directs central genetic programs of detoxification and protection against oxidative stress, increased rather than attenuated GSTP1 expression. In vitro investigations with mouse embryonic fibroblasts revealed factors, in addition to Nrf2, that control the expression of GSTP1, offering further insights into regulation. The new reporter mouse described here provides a useful tool to gain deeper insights into the mechanisms of action of chemopreventive compounds and other environmental agents.
authors.affiliation: Cancer Research UK Molecular Pharmacology Unit, Biomedical Research Institute, College of Medicine, Dentistry & Nursing, University of Dundee, Ninewells Hospital, Dundee, United Kingdom.
authors.forename: Colin J
authors.initials: CJ
authors.lastname: Henderson
authors.affiliation: Cancer Research UK Molecular Pharmacology Unit, Biomedical Research Institute, College of Medicine, Dentistry & Nursing, University of Dundee, Ninewells Hospital, Dundee, United Kingdom.
authors.forename: Aileen W
authors.initials: AW
authors.lastname: McLaren
authors.affiliation: Cancer Research UK Molecular Pharmacology Unit, Biomedical Research Institute, College of Medicine, Dentistry & Nursing, University of Dundee, Ninewells Hospital, Dundee, United Kingdom. c.r.wolf@dundee.ac.uk.
authors.forename: C Roland
authors.initials: CR
authors.lastname: Wolf
mesh_terms: D000818:Animals; D016588:Anticarcinogenic Agents / Q000494:pharmacology*; D004195:Disease Models, Animal; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects*; D020022:Genetic Predisposition to Disease; D051549:Glutathione S-Transferase pi / Q000096:biosynthesis* / Q000235:genetics; D006801:Humans; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D051267:NF-E2-Related Factor 2 / Q000235:genetics / Q000378:metabolism; D009369:Neoplasms / Q000139:chemically induced / Q000201:enzymology / Q000209:etiology / Q000235:genetics; D011401:Promoter Regions, Genetic; D014157:Transcription Factors / Q000378:metabolism
chemical_list: D016588:Anticarcinogenic Agents; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; C495636:Nfe2l2 protein, mouse; D014157:Transcription Factors; C496556:GSTP1 protein, human; D051549:Glutathione S-Transferase pi; C496557:Gstp1 protein, mouse