Glutathione S-transferases—biomarkers of cancer risk and chemopreventive response

Clapper, Margie L.; Szarka, Christine E.

doi:10.1016/s0009-2797(97)00174-9

Cited by 54 publications

(32 citation statements)

References 26 publications

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“…These results suggest that as NAFLD advances, patients may have a reduced capacity to combat the oxidative insults of electrophilic compounds. A similar phenomenon has been observed in a murine model of ulcerative colitis (Clapper and Szarka, 1998). Note that this downward trend in GST activity parallels the expression of GST M protein within our samples.…”

Section: Discussionsupporting

confidence: 89%

Diversity in Antioxidant Response Enzymes in Progressive Stages of Human Nonalcoholic Fatty Liver Disease

et al. 2010

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ABSTRACT:Nonalcoholic fatty liver disease (NAFLD), which occurs in approximately 17 to 40% of Americans, encompasses progressive stages of liver damage ranging from steatosis to nonalcoholic steatohepatitis (NASH). Inflammation and oxidative stress are known characteristics of NAFLD; however, the precise mechanisms occurring during disease progression remain unclear. The purpose of the current study was to determine whether the expression or function of enzymes involved in the antioxidant response, NAD(P)H:quinone oxidoreductase 1 (NQO1), glutathione transferase (GST), and glutamate cysteine ligase, are altered in the progression of human NAFLD. Human livers staged as normal, steatotic, NASH (fatty), and NASH (not fatty) were obtained from the Liver Tissue Cell Distribution System. NQO1 mRNA, protein, and activity tended to increase with disease progression. mRNA levels of the GST isoforms A1, A2, A4, M3, and P1 increased with NAFLD progression. Likewise, GST A and P protein increased with progression; however, GST M protein levels tended to decrease. Of interest, total GST activity toward the substrate 1-chloro-2,4-dinitrobenzene decreased with NAFLD progression. GSH synthesis does not seem to be significantly dysregulated in NAFLD progression; however, the GSH/ oxidized glutathione redox ratio seemed to be reduced with disease severity, indicating the presence of oxidative stress and depletion of GSH throughout progression of NAFLD. Malondialdehyde concentrations were significantly increased with disease progression, further indicating the presence of oxidative stress. Nuclear immunohistochemical staining of nuclear factor E2-related factor 2 (Nrf2), an indicator of activation of the transcription factor, was evident in all stages of NAFLD. The current data suggest that Nrf2 activation occurs in response to disease progression followed by induction of specific Nrf2 targets, whereas functionality of specific antioxidant defense enzymes seems to be impaired as NAFLD progresses.

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Section: Discussionsupporting

confidence: 89%

Diversity in Antioxidant Response Enzymes in Progressive Stages of Human Nonalcoholic Fatty Liver Disease

et al. 2010

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“…Our finding that GSH levels were associated with cytokine release in response to V. vulnificus has significance in terms of other clinical conditions known to be associated with susceptibility to V. vulnificus infection. While liver disease is not generally a clinical feature of diabetes, HIV infection, immunosuppressive therapy, or cancer, reduced levels of GSH are often reported (4,8,34,36,45). Perhaps it is the modulation of cellular thiol regulation and not liver disease per se that is associated in part with increased susceptibility to V. vulnificus among chronic alcohol users.…”

mentioning

confidence: 99%

Inflammatory Cytokine Response to Vibrio vulnificus Elicited by Peripheral Blood Mononuclear Cells from Chronic Alcohol Users Is Associated with Biomarkers of Cellular Oxidative Stress

et al. 2003

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Vibrio vulnificus is the leading cause of death in the United States associated with the consumption of raw seafood, particularly oysters. In epidemiological studies, primary septicemia and inflammation-mediated septic shock caused by V. vulnificus is strongly associated with liver disease, often in the context of chronic alcohol abuse. The present study was undertaken to determine whether clinical biomarkers of liver function or cellular oxidative stress are associated with peripheral blood mononuclear cell inflammatory cytokine responses to V. vulnificus. Levels of interleukin-1␤ (IL-1␤), IL-6, IL-8, and tumor necrosis factor alpha elicited in response to V. vulnificus and measured in cell supernatants were not associated with the liver biomarkers aspartate aminotransferase (AST) or alanine aminotransferase (ALT) or the AST/ALT ratio. Vibrio vulnificus is a gram-negative bacterium found commonly in marine and estuarine environments. In the United States, it predominates in the warm waters of the Gulf and Atlantic Coasts (25, 27, 28). Despite not being a notifiable disease, each year there are 20 to 50 reported cases of V. vulnificus primary septicemia in the United States, occurring most often following the consumption of naturally contaminated raw oysters (2, 14). V. vulnificus also has the ability to cause gastroenteritis, which is generally self-limiting, and wound infections in otherwise healthy individuals (17, 32). Primary septicemia is seen almost exclusively in people with an underlying condition affecting their immune system. In epidemiological studies, primary septicemia caused by V. vulnificus is most often associated with preexisting liver disease, although other conditions, such as diabetes mellitus, hemochromatosis, immunodeficiency, or malignancy, may also increase susceptibility to this organism (2,14,17,24,41). The impairment of iron metabolism and resultant iron overload associated with many of these conditions is thought to support increased V. vulnificus growth and reduced immune clearance (1, 15, 16). Primary septicemia caused by V. vulnificus appears to follow a classical septic shock pathway, including an overwhelming inflammatory cytokine response followed by multiorgan failure and death. Presently, there is no effective treatment for V. vulnificus once someone has developed primary septicemia, and death usually ensues. It should be noted that V. vulnificus has many similarities with other gram-negative, encapsulated, opportunistic bacterial pathogens and likely exploits similar host susceptibility pathways that could be targeted for intervention.To date, the majority of V. vulnificus studies have focused on the bacterial factors involved in disease (41). Therefore, while much is now known about some of the bacterial factors involved in the disease process, little is understood about host cellular factors leading to susceptibility. It has been previously shown that V. vulnificus has the ability to elicit inflammationassociated cytokines from primary human cells in vitro and from animals...

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“…GSTs plays an important role in protecting colonic epithelial cells against the effects of dietary mutagens and reactive oxygen species (Hayes and Pulford, 1995). Although the precise mechanisms are unclear, there is convincing evidence that the pathogenesis of inflammatory bowel disease is associated with increased oxidative damage due to a reduction in cytoprotection (Lih-Brody et al, 1996), including diminished GST activity (Bhaskar et al, 1995;Clapper and Szarka, 1998). Pro-inflammatory cytokines, notably tumor necrosis factor-␣, interleukin-1␤, and interleukin-6 are secreted by inflammatory cells and enterocytes during the intestinal inflammatory response (Stevens et al, 1992;Jung et al, 1995).…”

mentioning

confidence: 99%

Down-Regulation of Alpha Class GlutathioneS-Transferase by Interleukin-1β in Human Intestinal Epithelial Cells (Caco-2) in Culture

Romero

Higgins²,

Gilmore³

et al. 2002

Drug Metab Dispos

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ABSTRACT:The influence of pro-inflammatory cytokines on alpha class glutathione S-transferase A1 and A2 (GSTA1/A2) expression was examined in human colonic epithelial cells (Caco-2) in culture. Dose-dependent reductions in GSTA1/A2 mRNA, protein, and activity levels occurred in Caco-2 cells cultured in conditioned medium (CM) from lipopolysaccharide-stimulated murine monocyte-macrophage cells (RAW 264.7). Neutralizing anti-interleukin-1␤ (IL-1␤) antibodies attenuated this repression of GSTA1/A2 expression by CM. Moreover, recombinant human IL-1␤ reduced GST␣ expression at the mRNA, protein, and activity levels in a dose-related fashion. Reduction of GSTA1/A2 mRNA levels by IL-1␤ was attenuated by pretreatment with IL-1 receptor antagonist. GSTA1/A2 mRNA half-lives were similar in control and IL-1␤-treated cells, indicating that IL-1␤ has no effect on mRNA stability. In reporter gene studies, IL-1␤ caused a dose-related reduction of luciferase activity in Caco-2 cells transfected with the full-length GSTA1 promoter-luciferase construct. Using truncated constructs, IL-1␤ responsiveness was mapped to a region 286 base pairs upstream to the coding region. Deletion of a hepatic nuclear factor 1 (HNF-1) site in this region abrogated the IL-1␤-mediated repression of GSTA1 promoter activity. These results demonstrate that IL-1␤ down-regulates GSTA1/A2 expression in cultured human enterocytes by a transcriptional mechanism involving an HNF-1 site.

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Glutathione S-transferases—biomarkers of cancer risk and chemopreventive response

Cited by 54 publications

References 26 publications

Diversity in Antioxidant Response Enzymes in Progressive Stages of Human Nonalcoholic Fatty Liver Disease

Diversity in Antioxidant Response Enzymes in Progressive Stages of Human Nonalcoholic Fatty Liver Disease

Inflammatory Cytokine Response to Vibrio vulnificus Elicited by Peripheral Blood Mononuclear Cells from Chronic Alcohol Users Is Associated with Biomarkers of Cellular Oxidative Stress

Down-Regulation of Alpha Class GlutathioneS-Transferase by Interleukin-1β in Human Intestinal Epithelial Cells (Caco-2) in Culture

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