Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0019204 (hepatocellular carcinoma)
 71,386 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

1. Epoxide hydrolases form an enzyme family involved in the metabolism of a variety of xenobiotics including cytostatic drugs and carcinogens. Whether human microsomal epoxide hydrolase--one of the main members of the epoxide hydrolase family--is expressed in neoplasia of the liver has been the subject of a controversial discussion. 2. We therefore developed a quantitative immunohistochemical assay and monitored epoxide hydrolase expression in hepatocellular carcinomas (HCC, n = 20), cholangio-cellular carcinomas (CCC, n = 2) and liver metastases (n = 57) of tumours of various origins, and compared the expression intensities and patterns to normal liver tissue. 3. In normal liver tissue microsomal epoxide hydrolase displays expression of the constitutive type with non-zonal staining of all hepatocytes. 4. When using a quantitative immunohistochemical approach statistically significant differences in microsomal epoxide hydrolase expression were observed between normal tissue, hepatocellular carcinoma and liver metastases (mean optical density 2.35, 1.63 and 0.21 respectively, p = 2.9, 6.3 and 18.9). These data indicate differential expression in different types of liver neoplasm. 5. As microsomal epoxide hydrolase is involved in metabolism of different xenobiotics our findings may have implications for tumour progression.
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PMID:Immunohistochemical assessment of human microsomal epoxide hydrolase in primary and secondary liver neoplasm: a quantitative approach. 885 25

To identify environmental, viral, and genetic factors that may influence the risk of developing hepatocellular carcinoma (HCC), large prospective studies are being conducted in Haimen City, China and Senegal, and a case-control study of genetic variation in the detoxification of aflatoxin-B1 was carried out in Shanghai, China. Analysis of 78 HCCs that have occurred among 51,020 men enrolled in a large prospective study in Haimen City, China showed a strong association of HCC with chronic hepatitis B virus (HBV) infection. There were also significant associations of HCC risk with occupation (farming), history of a clinical episode of hepatitis in adulthood, and a family history of HCC. Study of 52 HCC cases and 116 controls for genetic polymorphisms and HCC risk showed a significant association with epoxide hydrolase (EPHX) mutant alleles (1/2, 2/2) and a borderline association with homozygous deletion of the glutathione-S-transferase mu (GSTM1) gene. There was a multiplicative interaction of these polymorphisms with chronic HBV infection such that HBsAg-positive persons who were GSTM1 null and were EPHX 1/2 or 2/2 had 135 times the risk of HCC as HBsAg-negative persons with the wild type genotypes for GSTM1 and EPHX. The risk of HCC is not uniform among persons with chronic HBV or HCV infections. Studies of genetic, viral, and environmental interactions may permit identification of those individuals at highest risk within groups at increased risk of HCC. Prevention strategies could then be targeted at those individuals.
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PMID:Molecular and genetic epidemiology of hepatocellular carcinoma: studies in China and Senegal. 887 9

Stereoselective epoxidation by cytochrome P450s (P450s) and regioselective hydration by epoxide hydrolase determine the carcinogenic potency of some polycyclic aromatic hydrocarbons (PAHs). In this report, cDNA-expressed human and mouse P450s 1A1 and 1A2 and epoxide hydrolase were used to characterize the stereoselective epoxidation and regioselective hydration at the K-region of benz[a]-anthracene (BA), 7,12-dimethylbenz[a]anthracene (DMBA), chrysene (CR), benzo[a]pyrene (B[a]P), dibenz[a,h]anthracene (DB[a,h]A), and benzo[c]phenanthrene (B[c]Ph) by direct chiral stationary-phase HPLC (CSP-HPLC) analyses. Our results indicated that all P450 isoforms preferentially produced major K-region, S,R-epoxides of BA (95-98%), DMBA (94-97%), B[a]P (91-96%), DB[a,h]A (94-98%), and B[c]Ph (87-92%), and major R,S-epoxide of CR (74-85%) in the presence of 3,3,3-trichloropropylene 1,2-oxide (TCPO), an inhibitor of epoxide hydrolase, suggesting that P450 enzymes exhibited the high stereoselectivity toward one of two stereoheterotopic faces of K-region double bond of the PAHs. Epoxide hydrolase either expressed from recombinant vaccinia virus or contained in human hepatoma G2 cells (HepG2) hydrated the C-O bond of epoxy-ring at the S-carbon of major metabolically-formed K-region epoxide enantiomers of BA, CR, DMBA, B[a]P, and DB[a,h]A to yield 80-98% dihydrodiols enriched in R,R-form and that at the R-carbon of B[c]Ph epoxide to yield 77-92% dihydrodiol enriched in S,S-form, suggesting that epoxide hydrolase was highly regioselective. The various enantiomeric components of dihydrodiol products in the metabolism of PAHs were apparently due to the combined effect of stereoselectivity of the P450s and regioselectivity of epoxide hydrolase. Our results provide a clear understanding of how these enzymes catalyze overall stereoselective metabolism at the K-region of the PAHs.
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PMID:Stereoselective epoxidation and hydration at the K-region of polycyclic aromatic hydrocarbons by cDNA-expressed cytochromes P450 1A1, 1A2, and epoxide hydrolase. 896 44

Induction of phase 2 enzymes (e.g., glutathione transferases, NAD(P)H:quinone reductase, glucuronosyltransferases, epoxide hydrolase) is a major strategy for reducing the susceptibility of animal cells to neoplasia and other forms of electrophile toxicity. In a search for new chemoprotective enzyme inducers, a structure-activity analysis was carried out on two types of naturally occurring and synthetic substituted phenylpropenoids: (a) Ar-CH=CH-CO-R, where R is OH, OCH3, CH3, or Ar, including cinnamic, coumaric, ferulic, and sinapic acid derivatives, their ketone analogues, and chalcones; and (b) bis(benzylidene)cycloalkanones, Ar-CH=C(CH2)n(CO)C=CH-Ar, where n = 5, 6, or 7. The potencies of these compounds in inducing NAD(P)H:quinone reductase activity in murine hepatoma cells paralleled their Michael reaction acceptor activity (Talalay, P.; De Long, M. J.; Prochaska, H. J. Proc. Natl. Acad. Sci. U.S.A. 85, 1988, 8261-8265). Unexpectedly, the bis(benzylidene)cycloalkanones also powerfully quenched the lucigenin-derived chemiluminescence evoked by superoxide radicals. Introduction of o-hydroxyl groups on the aromatic rings of these phenylpropenoids dramatically enhanced their potencies not only as inducers for quinone reductase but also as quenchers of superoxide. These potentiating o-hydroxyl groups are hydrogen-bonded, as shown by moderate downfield shift of their proton NMR resonances and their sensitivities to the solvent environment. The finding that the potencies of a series of bis(benzylidene)cycloalkanones in inducing quinone reductase appear to be correlated with their ability to quench superoxide radicals suggests that the regulation of phase 2 enzymes may involve both Michael reaction reactivity and radical quenching mechanisms.
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PMID:Chemoprotective properties of phenylpropenoids, bis(benzylidene)cycloalkanones, and related Michael reaction acceptors: correlation of potencies as phase 2 enzyme inducers and radical scavengers. 985 96

Aflatoxins together with chronic hepatitis B virus (HBV) infection contribute to the high incidence of hepatocellular carcinoma in developing countries. An understanding of the mechanism of interaction between these factors would provide a strong rationale for developing effective prevention strategies. In this study in The Gambia we examined the effect of environmental (place of residence and timing of sample collection) and host factors (age, sex, HBV status and interindividual variations in carcinogen metabolising enzymes) in determining blood aflatoxin-albumin adduct levels in 357 individuals of whom 181 were chronic HBV carriers. Samples were analysed for aflatoxin-albumin adducts, HBV status and genotypes of glutathione S-transferase (GST) M1, GSTT1, GSTP1 and epoxide hydrolase (EPXH). Urine samples were analysed for 6beta-hydroxycortisol:cortisol ratio as a marker of cytochrome P450 (CYP) 3A4 activity. Adduct levels were significantly higher in subjects resident in rural [geometric mean adduct level 34.9 pg aflatoxin B1-lysine equivalent (28.5-42.8; 95%CI)/mg albumin] than in periurban areas [22.2 pg (14.9-33.4)/mg] and were approximately twice as high in the dry season [mid-February to March; 83.2 pg (53.3-130.8)/mg] than the wet [July to August; 34.9 pg (28.5-42.8)/mg]. In contrast, HBV status, CYP3A4 phenotype, GSTT1, GSTP1 and EPXH genotypes were not associated with aflatoxin-albumin adduct level. However, mean adduct levels were significantly higher in non-HBV infected subjects with GSTM1 null genotype. The main factors which affect aflatoxin-albumin adduct levels in this population are environmental, notably place of residence and timing of sample collection. This study further emphasises the priority to reduce aflatoxin exposure in these communities by primary prevention measures.
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PMID:Environmental and genetic determinants of aflatoxin-albumin adducts in the Gambia. 1072 87

The gene encoding the xenobiotic-metabolising microsomal enzyme, epoxide hydrolase (mEPHX), shows two common mutations, i.e. at exons 3 and 4. It is unknown how these genetic polymorphisms relate to risk of developing alcoholic liver disease (ALD) and/or hepatocellular carcinoma (HCC) in a Caucasian population. DNA samples extracted from the blood of 61 ALD patients and 203 healthy controls, and from archival liver tissue of 46 cases of HCC, were subjected to polymerase chain reaction amplification followed by digestion with EcoR V or Rsa I to demonstrate polymorphisms of exon 3 or 4, respectively. The distributions of the genotypes of exon 3 in the ALD and HCC patients, and exon 4 in the HCC patients did not differ significantly from those of the control group. However, compared with the control group, the ALD group contained a significantly greater number of individuals homozygous or heterozygous for the exon 4 mutation. This suggested association between possession of the exon 4 mutant mEPHX allele and increased risk of developing ALD may relate to known interactions between mEPHX and alcohol-metabolising enzyme systems, or to linkage disequilibrium between the mutation and other genetic risk factors for ALD.
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PMID:Polymorphisms of the gene for microsomal epoxide hydrolase and susceptibility to alcoholic liver disease and hepatocellular carcinoma in a Caucasian population. 1081 27

Activities of microsomal monooxygenases (MO) and epoxide hydrolase (EH) and cytoplasmic glutathione-S-transferases (GST) will contribute to controlling the pool of reactive intermediates, enzymatically derived from polynuclear aromatic hydrocarbons (PAH) within the cells of target organs such as the human lung. Therefore, we studied what interindividual differences exist in these enzyme activities and whether there is a correlation between the activities of these epoxide forming and metabolizing enzymes in preparations from peripheral lung samples and the occurrence of bronchogenic carcinomas in smokers and non-smokers. 57 samples obtained from surgery were studied. Among them were 12 samples from non-smoking patients without cancer as a control group. It is not known whether this control group behaves, with respect to the investigated parameters, identically to fully healthy people, since in all cases indications existed which justified the removal of lung biopsies. Using very sensitive standard assays with benzo[a]pyrene, biphenyl, 7-ethoxyresorufin and 7-ethoxycoumarin as substrates, MO activity could only be determined as O-deethylation of 7-ethoxycoumarin and only after modification of the assay method. Evidence was obtained for the presence of a diffusible, but not dialysible, MO inhibitor in human lung microsomes. The MO activity (substrate: 7-ethoxycoumarin) in this fraction was extremely low in human (100-fold lower than in rat lung preparations), whereas EH (substrate: benzo[a]pyrene 4,5-oxide) was slightly (about 2-fold) higher in human and GST (substrate: 2,4-dinitrochlorobenzene) had similar activities in both species. Interindividual variations of enzyme activities in human lung were considerable: MO, 40-fold: EH, 5-fold; GST 10-fold. Compared to the control group (non-smokers without cancer) MO activities were slightly but significantly higher in lungs from bronchogenic carcinoma patients whether they were smokers (170% of controls, p < 0.0005) or non-smokers (320% of controls p < 0.025). MO activities of smokers without cancer were only very slightly elevated (140%) of controls, p < 0.05). Specific EH activities compared to the control group were slightly but significantly increased in smokers without cancer (160% of controls, p < 0.0125) and in bronchogenic carcinoma patients whether they used tobacco products (130% of controls, p < 0.005) or not (140% of controls, p < 0.05). Specific GST activities showed no significant differences (p > 0.1) between the various groups studied. The substrate specificity of human lung EH, which was studied using five K-region epoxides of various PAH as substrates, corresponded to that in human and rat liver and in human, mouse and rat skin and to the pure enzyme isolated from rat liver. In contrast to rat liver hepatoma preparations, where EH had been shown to be increased in the tumor tissue and had been identified as a preneoplastic antigen, EH activity in lung microsomal preparations from samples of peripheral squamous cell carcinomas of two subjects had in the tumor tissue only one third of the activity of non-diseased areas of the same lung.
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PMID:Monooxygenase, epoxide hydrolase, and glutathione-S-transferase activities in human lung. Variation between groups of bronchogenic carcinoma and non-cancer patients and interindividual differences. 1121 54

Polycyclic aromatic hydrocarbons (PAHs) are metabolized to trans-dihydrodiol proximate carcinogens by CYP1A1 and epoxide hydrolase (EH). CYP1A1 or aldo-keto reductases (AKRs) from the 1C subfamily can further activate the trans-dihydrodiols by forming either anti-diol-epoxides or reactive and redox active o-quinones, respectively. To determine whether other AKR superfamily members can divert trans-dihydrodiols to o-quinones, the cDNA encoding human aldehyde reductase (AKR1A1) was isolated from hepatoma HepG2 cells using RT-PCR, subcloned into a prokaryotic expression vector, overexpressed in E. coli and purified to homogeneity in milligram amounts. Studies revealed that AKR1A1 preferentially oxidized the metabolically relevant (-)-[3R,4R]-dihydroxy-3,4-dihydrobenz[a]anthracene. AKR1A1 also displayed high utilization ratios (V(max)/K(m)) for the following PAH trans-dihydrodiols: (+/-)trans-3,4-dihydroxy-3,4-dihydro-7-methylbenz[a]anthracene, (+/-)trans-3,4-dihydroxy-3,4-dihydro-7,12-dimethylbenz[a]anthracene and (+/-)trans-7,8-dihydroxy-7,8-dihydro-5-methylchrysene. Multiple tissue expression (MTE) arrays were used to measure the co-expressed of CYP1A1, EH and AKR1A1. All the three enzymes co-expressed to sites of PAH activation. The high catalytic efficiency of AKR1A1 for potent proximate carcinogen trans-dihydrodiols and its presence in tissues that contain CYP1A1 and EH suggests that it plays an important role in this alternative pathway of PAH activation (supported by CA39504).
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PMID:Metabolic activation of polycyclic aromatic hydrocarbon trans-dihydrodiols by ubiquitously expressed aldehyde reductase (AKR1A1). 1130 97

Exposure to aflatoxins is a risk factor for hepatocellular carcinoma (HCC). Aflatoxins occur in peanut butter and are metabolized by genetically polymorphic enzymes such as glutathione-S-transferases encoded by glutathione-S-transferase mu 1 gene (GSTM1) and glutathione-S-transferase theta 1 gene (GSTT1) and microsomal epoxide hydrolase encoded by epoxide hydrolase gene (EPHX). The rate at which aflatoxins become activated or detoxified may depend on polymorphisms in the encoding genes. GSTM1 homozygous deletion was indeed found to modify the association between peanut butter consumption and HCC. In this study, we investigate possible roles of GSTT1 and EPHX polymorphisms in this relationship. From a Sudanese case-control study on HCC, we analyzed data of 112 incident cases and 194 controls. All participants were interviewed using a standardized questionnaire inquiring about social and demographic factors, peanut butter consumption, and other known HCC risk factors. Univariate analysis showed that GSTT1 polymorphism was not associated with HCC, whereas EPHX 113HH and 139HH genotypes increased the risk of HCC (Odds ratio, 3.10; 95% Confidence interval, 1.18-8.12). Adjustment for age and region of origin slightly attenuated this association (Odds ratio, 2.56; 95% Confidence interval, 0.83-7.95). Interestingly, unlike GSTM1, both GSTT1 and EPHX polymorphism did not modify the association between peanut butter consumption and HCC. In conclusion, these epidemiological findings do not suggest significant roles of GSTT1 and EPHX in aflatoxin metabolism, although EPHX polymorphism is possibly related to the increased risk of HCC. Further studies are needed to investigate mechanisms by which the EPHX polymorphism potentially modifies cancer risk.
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PMID:Role of genetic polymorphism of glutathione-S-transferase T1 and microsomal epoxide hydrolase in aflatoxin-associated hepatocellular carcinoma. 1144 Sep 64

The genetic basis of disease susceptibility can be studied by several means, including research on animal models and epidemiological investigations in humans. The two methods are infrequently used simultaneously, but their joint use may overcome the disadvantages of either method alone. We used both approaches in an attempt to understand the genetic basis of aflatoxin B(1) (AFB(1))-related susceptibility to hepatocellular carcinoma (HCC). Ingestion of AFB(1) is a major risk factor for HCC in many areas of the world where HCC is common. Whether humans vary in their ability to detoxify the active intermediate metabolite of AFB(1), AFB(1)-exo-8,9-epoxide, is not certain but may explain why all exposed individuals do not develop HCC. To determine whether human variability in detoxification may exist, in a study of 231 HCC cases and 256 controls, we genotyped eleven loci in two families of AFB(1) detoxification genes; the glutathione S-transferases (GSTs) and the epoxide hydrolases (EPHX). After adjustment for multiple comparisons, only one polymorphism in the epoxide hydrolase family 2 locus remained significantly associated with HCC (odds ratio = 2.06, 95% confidence interval = 1.13-3.12). To determine whether additional susceptibility loci exist, we developed a mouse model system to examine AFB(1)-induced HCC. Susceptibility of 7-day-old mice from two common inbred strains (C57BL/6J, DBA/2J) was assessed. DBA/2J animals were 3-fold more sensitive to AFB(1)-induced HCC and significantly more sensitive to AFB(1) acute toxicity than were C57BL/6J animals. Analysis of the xenobiotic metabolizing genes in the two strains revealed single nucleotide polymorphisms in three genes, Gsta4, Gstt1, and Ephx1. Although the GSTT1 and EPHX1 loci did not appear to be related to HCC in the total population of the human study, a polymorphism in GSTA4 was significantly related to risk in the male subset. The mouse model also demonstrated that absent or compromised p53 was not necessary for the development of carcinogenesis. These results indicate that the comparison of results from human studies and the AFB(1)-susceptible mouse model may provide new insights into hepatocarcinogenesis.
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PMID:Susceptibility to aflatoxin B1-related primary hepatocellular carcinoma in mice and humans. 1290 37


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