Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: UMLS:C0596263 (carcinogenesis)
64,820 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Metabolic activation of 17beta-estradiol (E2) to catechols and quinones together with lack of deactivation constitute risk factors in human breast carcinogenesis. E2-catchols are generated by cytochrome P450-dependent monooxygenases (CYPs). Deactivation of E2, E2-catechols, and E2-quinones is mediated by UDP-glucuronosyltransferase (UGT), sulfotransferase (SULT), catechol-O-methyltransferase (COMT), glutathione-S-transferase (GST), and NADPH-quinone-oxidoreductase (QR) isozymes, respectively. The aim of the present study was to quantify mRNA levels of E2-metabolizing isozymes expressed in MCF-7 cells cultured in the presence/absence of steroids by reverse transcription/competitive PCR in relation to the housekeeping gene hypoxanthine-guanine phosphoribosyltransferase and compare them with expression levels in normal human mammary gland (MG) and liver tissue. CYP1A1, 1B1, SULT1A1, 1A2, membrane-bound and soluble COMT, GSTT1, QR1, and UGT2B7 were detected in both tissues and MCF-7 cells; however, most enzymes were expressed at least tenfold higher in liver. Yet, CYP1B1 was expressed as high in breast as in liver and UGTs were not detected in MCF-7 cells cultured with steroids. MCF-7 cells cultured steroid-free additionally expressed CYP1A2 as well as UGT1A4, 1A8, and 1A9. Normal human liver but not MG expressed CYP1A2, 3A4, UGT1A1, 1A3, 1A4, 1A9, and SULT2A1. UGT1A8 was only detected in MCF7 cells but was not found in human liver. Thus, our study provides a comprehensive overview of expression levels of E2-metabolizing enzymes in a popular in vitro model and in human tissues, which will contribute to the interpretation of in vitro studies concerning the activation/deactivation of E2.
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PMID:Gene expression of 17beta-estradiol-metabolizing isozymes: comparison of normal human mammary gland to normal human liver and to cultured human breast adenocarcinoma cells. 1849 89

The activation of 17beta-estradiol (E2) to 2-hydroxyestradiol (2-HO-E2), the more genotoxic 4-hydroxyestradiol (4-HO-E2), and the oxidation to the respective quinones constitutes a risk factor in hormonal carcinogenesis. 2-HO-E2 is formed by cytochrome P450 CYP1A1, and 4-HO-E2 is formed by CYP1B1. Both are detoxified by catechol-O-methyltransferase (COMT), whereas their quinones are inactivated by NADPH-quinone-oxidoreductase (QR). Since the soy isoflavones genistein (GEN) and daidzein (DAI) are widely consumed due to their putative protective function in breast carcinogenesis, we examined the influence of E2, GEN, and DAI on CYP1A1/1B1, COMT, and QR expression in MCF-7 cells by reverse transcription/competitive PCR. CYP1A1 and COMT enzyme activity were determined using ethoxyresorufin and quercetin as substrates. Furthermore, estrogen receptor (ER)-regulated cell proliferation was determined by E-screen. E2, GEN, and DAI inhibited the expression of CYP1A1, COMT, and QR. The maximum effect (reduction by 40-80%, depending on the gene product and compound) was obtained at 100 pM E2, 1 microM GEN, and 10 microM DAI, which also induced the most pronounced cell proliferation in the E-screen. In contrast, expression of CYP1B1 was only slightly affected. CYP1A1 and COMT mRNA levels correlated with enzyme activities. The ER antagonist ICI 182,780 reversed the E2- and isoflavone-mediated effects. Thus, GEN and DAI at estrogen-active concentrations stimulate the formation of the more E2 genotoxic metabolites and inhibit the detoxification of catechol and quinone estrogens in estrogen-responsive tumor cells.
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PMID:Phytoestrogens modulate the expression of 17alpha-estradiol metabolizing enzymes in cultured MCF-7 cells. 1849 90

The objective of this study was to evaluate the chemopreventive potential of the black tea polyphenols Polyphenon-B and BTF-35 during the preinitiation phase of 7,12-dimethylbenz[a]anthracene (DMBA)-induced hamster buccal pouch (HBP) carcinogenesis. Hamsters were divided into six groups. Animals in groups 2 and 3 received diet containing Polyphenon-B and BTF-35, respectively, 4 weeks before carcinogen administration when they were 6 weeks of age and continued until the final exposure to carcinogen. At 10 weeks of age, animals in groups 1, 2, and 3 were painted with 0.5% DMBA three times a week for 14 weeks. Animals in groups 4 and 5 were given Polyphenon-B and BTF-35 alone, respectively, as in groups 2 and 3. Animals in group 6 served as control. All the animals were sacrificed after an experimental period of 18 weeks. Phase I and phase II xenobiotic-metabolizing enzymes and 8-hydroxy-deoxyguanosine (8-OH-dG) in the buccal pouch and liver were used as biomarkers of chemoprevention. Hamsters painted with DMBA showed increased expression of 8-OH-dG and enhanced activities of phase I (CYP450; total as well as CYP1A1, 1A2, and 2B isoforms and cytochrome b5) and phase II (GST and quinone reductase) xenobiotic-metabolizing enzymes with increased immunohistochemical expression of CYP1A1, and CYP1B1 isoforms in the buccal pouch. This was accompanied by increased phase I and decreased phase II enzyme activities in the liver. Administration of Polyphenon-B and BTF-35 significantly decreased tumor incidence, oxidative DNA damage, phase I enzyme activities as well as expression of CYP1A1 and CYP1B1 isoforms, while enhancing phase II enzyme activities in the buccal pouch and liver. Our results provide a mechanistic basis for the chemopreventive potential of black tea polyphenols. Furthermore, the greater efficacy of BTF-35 in chemoprevention of HBP carcinomas via inhibition of oxidative DNA damage and modulation of xenobiotic-metabolizing enzymes may have a major impact in human oral cancer prevention.
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PMID:Pretreatment with black tea polyphenols modulates xenobiotic-metabolizing enzymes in an experimental oral carcinogenesis model. 1854 9

Tobacco smoking, alcohol drinking, and occupational exposures to polycyclic aromatic hydrocarbons are the major proven risk factors for human head and neck squamous-cell cancer (HNSCC). Major research focus on gene-environment interactions concerning HNSCC has been on genes encoding enzymes of metabolism for tobacco smoke constituents and repair enzymes. To investigate the role of genetically determined individual predispositions in enzymes of xenobiotic metabolism and in repair enzymes under the exogenous risk factor tobacco smoke in the carcinogenesis of HNSCC, we conducted a case-control study on 312 cases and 300 noncancer controls. We focused on the impact of 22 sequence variations in CYP1A1, CYP1B1, CYP2E1, ERCC2/XPD, GSTM1, GSTP1, GSTT1, NAT2, NQO1, and XRCC1. To assess relevant main and interactive effects of polymorphic genes on the susceptibility to HNSCC we used statistical models such as logic regression and a Bayesian version of logic regression. In subgroup analysis of nonsmokers, main effects in ERCC2 (Lys751Gln) C/C genotype and combined ERCC2 (Arg156Arg) C/A and A/A genotypes were predominant. When stratifying for smokers, the data revealed main effects on combined CYP1B1 (Leu432Val) C/G and G/G genotypes, followed by CYP1B1 (Leu432Val) G/G genotype and CYP2E1 (-70G>T) G/T genotype. When fitting logistic regression models including relevant main effects and interactions in smokers, we found relevant associations of CYP1B1 (Leu432Val) C/G genotype and CYP2E1 (-70G>T) G/T genotype (OR, 10.84; 95% CI, 1.64-71.53) as well as CYP1B1 (Leu432Val) G/G genotype and GSTM1 null/null genotype (OR, 11.79; 95% CI, 2.18-63.77) with HNSCC. The findings underline the relevance of genotypes of polymorphic CYP1B1 combined with exposures to tobacco smoke.
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PMID:Head and neck squamous-cell cancer and its association with polymorphic enzymes of xenobiotic metabolism and repair. 1856 91

Polychlorinated biphenyls (PCBs) are classified by the International Agency for Research on Cancer as probable human carcinogens. A subset of PCBs are described as 'dioxin like' because of similarities to 2,3,7,8-tetrachlorodibenzo-p-dioxin. Dioxin-like PCBs have been shown to tightly bind the active site of cytochrome P450 (CYP) 1A isoforms, primarily CYP1A1, resulting in inhibition of CYP activity and the generation of reactive oxygen species (ROS) as a result of uncoupling of the catalytic cycle. Human CYP1B1 (hCYP1B1) is an extrahepatic CYP closely related to hCYP1A1 and is overexpressed in the lungs of smokers. Moreover, hCYP1B1 has been found to be overexpressed in cancers derived from a number of tissue types, as well as in pre-malignant prostate tumours, implicating overexpression of hCYP1B1 as a risk factor for extrahepatic carcinogenesis. It has been demonstrated previously that hCYP1B1 is inhibited by dioxin-like PCBs, but whether or not it is uncoupled has not been investigated. In the current study, the ability of three dioxin-like PCBs 3,3',4,4'-tetrachlorobiphenyl, 3,3',4,4',5-pentachlorobiphenyl and 3,3',4,4',5,5'-hexachlorobiphenyl (PCB169) to inhibit hCYP1B1 and stimulate the formation of ROS in V79MZ cells (which lack endogenous CYPs) expressing hCYP1B1 was demonstrated. Moreover, the generation of ROS was also associated with increases in parameters of oxidative stress related to genotoxicity (DNA oxidation and lipid peroxidation). For PCB169, these effects were time and concentration dependent. These data identify a novel mechanism of genotoxicity for dioxin-like PCBs, as well as providing further evidence that overexpression of hCYP1B1 is a risk factor for extrahepatic carcinogenesis.
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PMID:Reactive oxygen species from the uncoupling of human cytochrome P450 1B1 may contribute to the carcinogenicity of dioxin-like polychlorinated biphenyls. 1858 86

Aromatic amines (AAs) and polycyclic aromatic hydrocarbons (PAHs) are carcinogens present in tobacco smoke and functional polymorphisms in NAT2 and GSTM1 metabolizing genes are associated with increased bladder cancer risk. We evaluated whether genetic variation in other candidate metabolizing genes are also associated with risk. Candidates included genes that control the transcription of metabolizing genes [aryl hydrocarbon receptor (AHR), AHRR and aryl hydrocarbon nuclear translocator (ARNT)] and genes that activate/detoxify AA or PAH (AKR1C3, CYP1A1, CYP1A2, CYP1B1, CYP3A4, EPHX1, EPHX2, NQO1, MPO, UGT1A4, SULT1A1 and SULT1A2). Using genotype data from 1150 cases of urothelial carcinomas and 1149 controls from the Spanish Bladder Cancer Study, we estimated odds ratios (ORs) and 95% confidence intervals (CIs) adjusting for age, gender, region and smoking status. Based on a test for trend, we observed 10 non-redundant single-nucleotide polymorphisms (SNPs) in five genes (AKR1C3, ARNT, CYP1A1, CYP1B1 and SULT1A2) significantly associated with bladder cancer risk. We observed an inverse association with risk for the AKR1C3 promoter SNP rs1937845 [OR (95% CI) for heterozygote and homozygote variant compared with common homozygote genotype were 0.86 (0.70-1.06) and 0.74 (0.57-0.96), respectively; P for trend = 0.02]. Interestingly, genetic variation in this region has been associated with lung, non-Hodgkin lymphoma and prostate cancer risk. Analysis of additional SNPs to capture most (approximately 90%) of common genetic variation in AKR1C3 and haplotype walking analyses based on all AKR1C3 SNPs (n = 25) suggest two separate regions associated with bladder cancer risk. These results indicate that genetic variation in carcinogen-metabolizing genes, particularly AKR1C3, could be associated with bladder cancer risk.
Carcinogenesis 2008 Oct
PMID:Bladder cancer risk and genetic variation in AKR1C3 and other metabolizing genes. 1863 53

It is widely accepted that the cytotoxicity and genotoxicity of benzene results from the action of reactive metabolites. Therefore, genetic variation in metabolic enzyme genes may contribute to susceptibility to chronic benzene poisoning (CBP) in the exposed population. Using a case-control study that included 268 benzene-poisoned patients and 268 workers occupationally exposed to benzene in South China, we aimed to investigate the association between single-nucleotide polymorphisms in genes with phase I and II of metabolism and risk of CBP. The TaqMan technique was used to detect polymorphisms of CYP1A1, CYP1A2, CYP1B1, ADH1B, EPHX1, EPHX2, NQO1, MPO, GSTP1 and UGT1A6 genes. We also explored potential interactions of these polymorphisms with lifestyle factors such as cigarette smoking and alcohol consumption. A weak positive association was found between glutathione S-transferase pi-1 (GSTP1) rs1695 polymorphism and the risk of CBP (P = 0.046), but this association was not statistically significant (P = 0.117) after adjustment for potential confounders. Further analysis showed that the risk of CBP increased in the subjects with EPHX1 GGAC/GAGT diplotype (P = 0.00057) or AGAC/GAGT diplotype (P = 0.00086). In addition, we found that alcohol drinkers with the EPHX1 rs3738047 GA + AA genotypes and non-alcohol drinkers with the GSTP1 rs1695 AA genotype tended to be more susceptible to benzene toxicity. Our results suggest that genetic polymorphisms in EPHX1 may contribute to risk of CBP in a Chinese occupational population.
Carcinogenesis 2008 Dec
PMID:Polymorphisms in phase I and phase II metabolism genes and risk of chronic benzene poisoning in a Chinese occupational population. 1878 59

The present study was designed to evaluate the in vitro antioxidant potential of bovine lactoferrin (bLF) and black tea polyphenols [Polyphenon-B (P-B)] as well as in vivo inhibitory effects on the development of 7,12-dimethylbenz[a]anthracene (DMBA)-induced hamster buccal pouch (HBP) carcinomas. Antioxidant activity was screened using a panel of assays including 1,1-diphenyl-2-picrylhydrazyl (DPPH), 2,2'-azinobis-(3-ethyl-benzothiazoline-6-sulfonic acid) (ABTS), hydroxyl radical anion (OH*), superoxide anion (O2*-), and nitric oxide (NO) radical scavenging assays as well as assay for reducing power. The chemopreventive potential of bLF and P-B was assessed in the HBP model based on the modulatory effects on DMBA-induced oxidative DNA damage as well as the expression of proteins associated with carcinogen activation (CYP1A1, CYP1B1), cell proliferation [cyclin D1, proliferating cell nuclear antigen (PCNA), glutathione S-transferase pi (GST-P)], angiogenesis [vascular endothelial growth factor (VEGF), VEGF receptor 1 (VEGFR1)], and invasion and metastasis [matrix metalloproteinase-9 (MMP-9) and tissue inhibitors of MMP-2 (TIMP-2)]. Both bLF and P-B showed high radical scavenging activity and reductive potential. Although administration of bLF and P-B alone suppressed DMBA-induced HBP tumors, combined administration of bLF and P-B was more effective in inhibiting HBP carcinogenesis by inhibiting oxidative DNA damage, carcinogen activation, cell proliferation, invasion, and angiogenesis. Our study suggests that the antioxidative property of bLF and P-B may be responsible for chemoprevention of HBP carcinogenesis by modulating multiple molecular targets.
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PMID:In vitro antioxidative potential of lactoferrin and black tea polyphenols and protective effects in vivo on carcinogen activation, DNA damage, proliferation, invasion, and angiogenesis during experimental oral carcinogenesis. 1898 16

Androgens and estrogens may play a role in gastric cancer etiology. To investigate the association of gastric cancer with single-nucleotide polymorphisms (SNPs) in six genes (COMT, CYP1B1, CYP17A1, CYP19A1, HSD17B1 and SHBG) involved in estrogen and androgen synthesis and metabolism, 58 haplotype-tagging SNPs were genotyped in 295 gastric cancer cases and 415 controls from a population-based study in Poland. We assessed differences in haplotype frequency between cases and controls using a global score test and calculated multivariate odds ratios (ORs) and 95% confidence intervals (CIs) for individual haplotypes using logistic regression. We found associations in one linkage disequilibrium (LD) block containing the 3' untranslated region of COMT (rs9332377, rs165728, rs165849 and rs1110478), global score test (df = 4, P = 0.033). Relative to the most frequent GATA haplotype, the GATG haplotype was associated with statistically significant increased gastric cancer risk (OR = 1.50, 95% CI: 1.06-2.12; false discovery rate (FDR) value = 0.459) and the AACA haplotype with borderline increased risk (OR = 1.36, 95% CI = 1.00-1.85; FDR = 0.50). We also found associations for the LD block containing part of the SHBG coding region (rs6258, rs6259, rs2955617, rs1641544 and rs1641537). The CACCC haplotype was associated with statistically significant lower gastric cancer risk relative to the referent CGACC haplotype (OR = 0.55, 95% CI = 0.34-0.90; FDR = 0.459), but the overall score test was statistically non-significant. No other statistically significant associations were observed. In summary, we found possible associations between gastric cancer and polymorphisms in COMT, involved in estrogen inactivation, and SHBG, a modulator of hormone bioavailability. These findings should be interpreted cautiously until replicated in other studies.
Carcinogenesis 2009 Jan
PMID:Polymorphisms in estrogen- and androgen-metabolizing genes and the risk of gastric cancer. 1901

Southeast Asian women have a lower incidence of breast cancer than their counterparts in the West. Epidemiological studies have indicated that soya consumption may be a contributing factor. Carcinogenesis is a process involving multiple stages. The present review attempts to fit the cellular mechanisms attributed to soya isoflavones into these different stages. Many cell-culture studies have reported the growth-inhibitory effect of soya isoflavones; however, with the non-physiological concentrations employed in these studies it would be difficult to explain the protection mechanisms observed in epidemiological studies. Our laboratory has previously found that genistein inhibits cytochrome P450 (CYP)1A1 and CYP1B1. The inhibition implies that soya consumption may have the potential to prevent chemical carcinogenesis. The preferential inhibition of CYP1B1 may also block the oestrogen-initiated carcinogenesis. The antagonism of oestrogen receptor (ER) binding can affect the cell-proliferative phase, which is likely to be important in the promotion stage of breast cancer. Since our laboratory and others have indicated that genistein at physiological concentrations has no effect on the downstream activities of ER binding, the antagonism of ER is not likely to be a contributing factor in the disease prevention. Moreover, soya isoflavones cannot inhibit aromatase (CYP19), which is the enzyme responsible for oestrogen synthesis. In the present review various cellular activities altered by soya isoflavones are discussed.
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PMID:Dietary soya isoflavones and breast carcinogenesis: a perspective from a cell-culture model. 1907 5


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