Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.5.1.18 (glutathione S-transferase)
 22,582 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Chronic pancreatitis and pancreatic cancer have both been linked with occupational exposure to organic chemicals. These chemicals are known to be metabolized within the liver by the cytochrome P-450 family of enzymes, and indeed are able to induce levels of these enzymes as evidence of their interaction. The purpose of this study was therefore to see if these enzyme systems were altered in chronic pancreatitis and pancreatic cancer. Immunocytochemistry of four phase I drug-metabolizing enzymes (cytochromes P-450 IIIA1, P-450 IIE, P-450 IA2, and NADPH cytochrome P-450 oxido-reductase) and one phase II enzyme [glutathione S-transferase (GST) 5-5] was therefore performed on pancreas and/or liver biopsy samples from organ donors and compared with patients with chronic pancreatitis or pancreatic cancer. In samples from donor subjects, the types and levels of drug-metabolizing enzymes in hepatocytes were similar to those seen in pancreatic acinar cells. In material from patients with chronic pancreatitis or pancreatic cancer, cytochrome P-450 enzyme levels were greater in both the liver and the pancreas than those seen in the donor group, while GST levels were unchanged. Islets of Langerhans showed high levels of P-450 IA2 in the donor group, with clear induction of P-450 IIIA1 and NADPH cytochrome P-450 oxidoreductase in patients with chronic pancreatitis but not in the pancreatic cancer group. Levels of GST 5-5 were also induced in the islets. The present findings raise the possibility of an aetiological relationship between elevated levels of drug-metabolizing enzymes and the subsequent development of disease.
 ...
PMID:Induction of drug-metabolizing enzymes in human pancreatic cancer and chronic pancreatitis. 850 44

Class Alpha glutathione S-transferases (GST-Alpha) are found in high concentrations in human liver. Increased plasma concentrations of GSTA1-1, the most abundant isoform of GST-Alpha, are a very sensitive marker for hepatocellular leakage. A sandwich-type ELISA was developed, based on a monoclonal antibody specific for human GSTA1-1 and a polyclonal rabbit anti-human GST-Alpha antiserum. The assay is specific for human GSTA1-1, and has a detection limit of 0.04 micrograms/L. The distribution of plasma GSTA1-1 concentrations in 350 blood donors was nearly normalized by logarithmic transformation and an upper normal reference concentration of 5.9 micrograms/L was calculated. Men had significantly higher plasma GSTA1-1 concentrations than women (P <0.0001). In women, but not in men, a significant increase was noted with age (P <0.05). In patients with inflammatory bowel disease (n= 210), gastrointestinal tumors (n= 70), irritable bowel disease (n= 36), or chronic pancreatitis (n= 12), plasma GSTA1-1 concentrations were similar to those of controls. In contrast, plasma GSTA1-1 concentrations were increased to a similar extent as alanine aminotransferase activities in patients with liver disorders (n= 37).
 ...
PMID:Sandwich ELISA for glutathione S-transferase Alpha 1-1: plasma concentrations in controls and in patients with gastrointestinal disorders. 859 5

The mechanism of tissue alteration in chronic pancreatitis (CP) is still unclear. Different hypotheses have been discussed, including increasing oxidant stress in the acinar cells, often as a result of exposure to xenobiotics. To evaluate the role of oxidative stress in CP, the authors investigated the expression of the drug-metabolizing phase II enzyme, glutathione S-transferase-pi (GST-pi), in the pancreatic tissue of patients with CP and compared it with the healthy pancreatic tissue from age-matched donors. Pancreatic tissue from patients with secondary CP resulting from ductal obstruction by pancreatic cancer (PC) was also examined. The percentage of cells immunoreacting with anti-GST-pi was counted within 15 randomly selected islets in each slide of the three groups. In all specimens, ductal and ductular cells, and in PC, cancer cells, expressed GST-pi in a moderate intensity. Acinar cells did not stain. Various numbers of islet cells in each of the three groups were stained strongly. More islet cells expressed GST-pi in CP (42%) than in healthy pancreatic tissue (16%, p < 0.001) or PC (17%, p < 0.001). Our results imply an important role of islet cells in the metabolism of substances, which are the substrate for GST-pi, and lend support to the hypothesis of oxidative stress as the cause of CP.
 ...
PMID:Increased expression of glutathione S-transferase-pi in the islets of patients with primary chronic pancreatitis but not secondary chronic pancreatitis. 1134 40

Epidemiological studies have demonstrated a variety of potential environmental factors that may alter susceptibility to chronic pancreatitis (CP) through oxidative/xenobiotic stress; however, a direct causal and mechanistic role has not been established. We aimed (1) to determine the prevalence of functional genetic polymorphisms in the antioxidant enzymes, glutathione S-transferase GSTM-1, GSTP-1, and GSTT-1, manganese superoxide dismutase, and catalase in CP and (2) to reveal evidence of oxidative stress in patients with CP by measuring whole-blood glutathione redox status. In total, 122 patients with CP (75 alcohol-induced [A1CP], 33 idiopathic [ICP], and 13 hereditary) and 245 age- and sex-matched controls were recruited. The prevalence of the functional GSTT-1 genotype (GSTT-1*A) was significantly higher in CP (88.5%) compared to healthy controls (76%; chi2 = 7.26, P = 0.007). Stratification to disease etiology demonstrated that the GSTT-1*A genotype was also significantly more prevalent among patients with ICP (94%; P = 0.02; 95% CI, 0.04-9.16) but not in those with A1CP. In 22 patients with stable CP, the whole-blood glutathione concentration (median [IQR]: 72 micromol/L [21-181 micromol/L]) and the glutathione redox ratio (GSH/GSSG) (median [IQR]: 9 (3-77]) were significantly reduced compared to those in 20 healthy volunteers (median [IQR]: 815 micromol/L [679-1148 micromol/L], P < 0.001, and 96 [52-347], P = 0.005, respectively). We conclude that the GSTT-1 functional genotype is associated with ICP. Evidence of altered glutathione redox status suggests that this disease modification may be a consequence of oxidative stress or the bioactivation of xenobiotics.
 ...
PMID:Genetic polymorphisms of GSTT1, GSTM1, GSTP1, MnSOD, and catalase in nonhereditary chronic pancreatitis: evidence of xenobiotic stress and impaired antioxidant capacity. 1604 90

Findings obtained from numerous prospective cohort and case-control studies on alcohol consumption and pancreatic cancer risk have been inconsistent, with many confounding variables present in various investigations. However, heavy alcohol consumption has been known to be a major cause of chronic pancreatitis and a risk factor for type 2 diabetes mellitus, both of which are linked to pancreatic cancer. It has been established that an extensive normal interaction exists between the exocrine and endocrine pancreas, as well as in inflammatory processes and carcinogenesis. Alcohol and its metabolites (acetaldehyde and fatty acid ethyl esters) can alter metabolic pathways involved in the inflammatory response and carcinogenesis, and they are mediated by one or more of the following mechanisms: (1) premature activation of zymogens; (2) induction of the inflammatory response through activation of nuclear transcription factors, including nuclear factor-kappa and activation protein 1; (3) increased production of reactive oxygen species, resulting in oxidative DNA damage and altered effect of dietary antioxidants; (4) activation of pancreatic stellate cells, which leads to fibrosis; (5) gene mutation in enzymes related to cytochrome P450, glutathione S-transferase, aldehyde dehydrogenase, cationic trypsinogen, and pancreatic secretory trypsin inhibitor; (6) synergistic effects of ethanol and tobacco carcinogen on NNK [nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone] metabolism; and (7) dysregulation of proliferation and apoptosis. These various metabolic effects of alcohol can lead to or interact with other risk factors (genetic, dietary, environmental, and lifestyle factors) that result in acute and chronic pancreatitis and diabetes mellitus and, ultimately, affect the multistep process of carcinogenesis toward the development of pancreatic cancer.
 ...
PMID:Alcohol and pancreatic cancer. 1605 82