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. Cancer Res; 74(16); 4378-87. Ó2014 AACR.

Altered ProteinS-Glutathionylation Identifies a Potential Mechanism of Resistance to Acetaminophen-Induced Hepatotoxicity

“…A number of transcription binding sites, such as AP-1 (Moffat et al, 1997), p53 (Lo et al, 2008), retinoic acid, and nuclear factor kB (Xia et al, 1993), have been identified within the human GSTP gene. Recently, we have made further efforts to characterize the regulation of human GSTP1 in an animal model and demonstrated upregulation of human hepatic GSTP expression in response to the chemopreventive agents ethoxyquin and butylated hydroxyanisole (Henderson et al, 2014). Therefore, hepatic GSTP induction through chemical toxicity or hepatic disease may contribute to the known increase in the risk of drug-induced liver injury associated with APAP in these instances.…”

“…Mice livers were removed, washed in PBS, and fixed in 10% formalin before being embedded in paraffin wax. Sections (5 mm) were prepared and stained using hematoxylin and eosin to determine structural damage, as previously described (Henderson et al, 2014).…”

“…Cryosections (15 mm) were prepared using a Bright Instruments cryostat (Bright Instruments, Huntingdon, Cambridgeshire, UK), and sections were stained for b-galactosidase activity, as previously described (Henderson et al, 2014).…”

Proteomic analysis of 3-MCPD and 3-MCPD dipalmitate-induced toxicity in rat kidney

“…Gstp1 expression is, among other GSTs, regulated by Nrf2 (Gorrini et al 2013). However, upregulation of Gstp1 is also possible in the absence of Nrf2, as demonstrated in vivo in Nrf2 knockout mice (Henderson et al 2014;Satoh et al 2002). Gstp1 appears to be a sensitive early marker for kidney injury by 3-MCPD or 3-MCPD dipalmitate.…”

Expressão da glutationa S-transferase pi em pacientes com carcinoma epidermóide de cabeça e pescoço conforme os hábitos tabágico e etílico

“…Outros estudos descreveram que as GSTPI são expressas em tecido normal do trato digestório, urinário e respiratório, o que sustenta seu papel na eliminação de substâncias tóxicas mesmo em tecido não tumoral. Alterações histológicas de transição pré-neoplásica entre margem e tumor não foram evidenciadas no nosso estudo (Terrier et al, 1990;Geisler et al, 2005;Henderson et al, 2014).…”