Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0282612 (PIN)
 2,291 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The GSTP1 gene encodes for an enzyme, glutathione S-transferase pi (GSTpi),involved in detoxification of carcinogens. An aminoacid substitution (I105V) in GSTP1 produces a variant enzyme with lower activity and less capability of effective detoxification. This variant GSTP*B allele has been associated with a propensity to develop several neoplasms. Because GSTP1 promoter hypermethylation and inactivation of GSTpi expression is a frequent alteration in prostate carcinoma, we hypothesized that this somatic epigenetic modification could obviate any reduced enzyme activity caused by the germ-line polymorphism. We tested for the GSTP1 genotype in a population of prostate cancer patients, and in a control group composed of patients with benign prostatic hyperplasia (BPH) and healthy blood donors. Tissue samples from the 105 prostate cancer cases (105 adenocarcinomas and 34 prostatic intraepithelial neoplasia lesions), and from 43 BPH patients were tested for GSTP1 hypermethylation by methylation-specific PCR. GSTpi protein expression was assessed by immunohistochemistry. No significant effect on prostate cancer risk was detectable for GSTP1 genotype compared with the control population (odds ratio, 1.02; 95% confidence interval, 0.59-1.75). Moreover, no association was found between this genotype and tumor or BPH methylation status. Patients with unmethylated carcinomas did not disclose significant differences in genotypic distribution compared with the control population. In adenocarcinoma, a strong association (P < 0.00001) between GSTP1 promoter hypermethylation and loss of GSTpi expression was observed; however, this trend was not retained in prostatic intraepithelial neoplasia or BPH lesions. Although the GSTP1 polymorphism is not associated with altered susceptibility to prostate cancer, somatic promoter hypermethylation is an effective, but not the only, cause of decreased GSTpi function.
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PMID:I105V polymorphism and promoter methylation of the GSTP1 gene in prostate adenocarcinoma. 1201 Aug 58

2-amino-1-methyl-6-phenylimidazo(4,5-b)pyridine (PhIP) has been implicated as a major mutagenic heterocyclic amine in the human diet and is carcinogenic in the rat prostate. To validate PhIP-induced rat prostatic neoplasia as a model of human prostate cancer progression, we sought to study the earliest histologic and morphologic changes in the prostate and to follow progressive changes over time. We fed sixty-seven 5-week-old male Fischer F344 rats with PhIP (400 ppm) or control diets for 20 weeks, and then sacrificed animals for histomorphologic examination at the ages of 25, 45, and 65 weeks. Animals treated with PhIP showed significantly more inflammation (P = .002, > .001, and .016 for 25, 45, and 65 weeks, respectively) and atrophy (P = .003, > .001, and .006 for 25, 45, and 65 weeks, respectively) in their prostate glands relative to controls. Prostatic intraepithelial neoplasia (PIN) occurred only in PhIP-treated rats. PIN lesions arose in areas of glandular atrophy, most often in the ventral prostate. Atypical cells in areas of atrophy show loss of glutathione S-transferase pi immunostaining preceding the development of PIN. None of the animals in this study developed invasive carcinomas, differing from those in previous reports. Overall, these findings suggest that the pathogenesis of prostatic neoplasia in the PhIP-treated rat prostate proceeds from inflammation to postinflammatory proliferative atrophy to PIN.
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PMID:Inflammation and atrophy precede prostatic neoplasia in a PhIP-induced rat model. 1698 28

The Noble rat is an established model for studying hormone-induced development of prostatic intraepithelial neoplasia and prostatic adenocarcinoma. It is known that for a period, hormones in the prostate generate reactive molecules that have the capacity to overwhelm intracellular defenses, damage macromolecules, and modulate redox-regulated signaling pathways leading to increased oxidative stress. Such hormone-induced imbalance in the oxidative stress/antioxidant defense enzymes may lead to neoplastic transformation of the prostate. We investigated alteration in the expression of critical antioxidant defense enzymes, a redox-regulated transcription factor nuclear factor kappaB (NFkappaB) and its downstream target inflammation-associated cyclooxygenase 2 (Cox-2) in the prostate from hormone-stimulated Noble rats using immunohistochemistry. Further, we also analyzed serum levels of cytokines and chemokines associated with inflammation using multiplex immunoassay. Our results show that there was no significant change in the expression of glutathione peroxidase, glutathione S-transferase pi, superoxide dismutase, or catalase. However, the level of NADPH quinone oxidoreductase decreased in hormone-stimulated animals compared with their unstimulated counterparts. Further, the prostate from hormone-stimulated rats showed very strong expressions of p65, Cox-2, and NFkappaB DNA binding activity. In addition, the cytokine-induced neutrophil chemoattractant 2alpha was significantly upregulated by more than 10-fold (P = .001) in serum from animals stimulated with hormones. Although further studies are required, we speculate that activation of NFkappaB/cytokine-induced neutrophil chemoattractant 2alpha/Cox-2 along with modulation of antioxidant defense mechanisms may create a proinflammatory environment suitable for tumor growth and survival.
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PMID:Loss of NADPH quinone oxidoreductase in the prostate and enhanced serum levels of cytokine-induced neutrophil chemoattractant 2alpha in hormone-stimulated noble rats: potential role in prostatic intraepithelial neoplasia development. 1941 21