Objective To explore the function and mechanism of related genes in the occurrence and development of liver cancer, and the possibility of key genes as potential biomarkers and prognostic indicators for the treatment of liver cancer.Methods We selected 4 datasets(GSE57957, GSE121248, GSE36376 and GSE14520)from the GEO database.With
Biomarkers, Tumor/genetics* ; Carrier Proteins ; Computational Biology ; Cytochrome P-450 CYP2E1 ; Cytochrome P-450 CYP3A ; Gene Expression Profiling ; Gene Expression Regulation, Neoplastic ; Gene Regulatory Networks ; Glycoproteins ; Humans ; Liver Neoplasms/genetics* ; Prognosis ; Protein Interaction Maps

Mitochondrion-localized retinol dehydrogenase 13 (Rdh13) is a short-chain dehydrogenase/reductase involved in vitamin A metabolism in both humans and mice. We previously generated Rdh13 knockout mice and showed that Rdh13 deficiency causes severe acute retinal light damage. In this study, considering that Rdh13 is highly expressed in mouse liver, we further evaluated the potential effect of Rdh13 on liver injury induced by carbon tetrachloride (CCl). Although Rdh13 deficiency showed no significant effect on liver histology and physiological functions under regular culture, the Rdh13 mice displayed an attenuated response to CCl-induced liver injury. Their livers also exhibited less histological changes and contained lower levels of liver-related metabolism enzymes compared with the livers of wild-type (WT) mice. Furthermore, the Rdh13 mice had Rdh13 deficiency and thus their liver cells were protected from apoptosis, and the quantity of their proliferative cells became lower than that in WTafter CCl exposure. The ablation of Rdh13 gene decreased the expression levels of thyroid hormone-inducible nuclear protein 14 (Spot14) and cytochrome P450 (Cyp2e1) in the liver, especially after CCl treatment for 48 h. These data suggested that the alleviated liver damage induced by CCl in Rdh13 mice was caused by Cyp2e1 enzymes, which promoted reductive CCl metabolism by altering the status of thyroxine metabolism. This result further implicated Rdh13 as a potential drug target in preventing chemically induced liver injury.
Alcohol Oxidoreductases ; deficiency ; genetics ; Animals ; Carbon Tetrachloride Poisoning ; enzymology ; Chemical and Drug Induced Liver Injury ; enzymology ; pathology ; Cytochrome P-450 CYP2E1 ; metabolism ; Female ; Immunohistochemistry ; Liver ; drug effects ; enzymology ; pathology ; Male ; Mice ; Mice, 129 Strain ; Mice, Inbred C57BL ; Mice, Knockout ; Nuclear Proteins ; metabolism ; Transcription Factors ; metabolism

<p>OBJECTIVETo investigate the cytochrome P450 2E1 (CYP2E1) RsaI/PstI and DraI polymorphisms in workers exposed to benzene.p><p>METHODSA cross-sectional survey was carried out. A total of 71 workers exposed to benzene were included in observation group and the same number of people without occupational benzene exposure were included in control group. Blood samples from the two groups were collected and genotyping for CYP2E1 RsaI/PstI and DraI were conducted using the polymerase chain reaction-restriction fragment length polymorphism.p><p>RESULTSThere were no significant differences in CYP2E1 DraI genotype and allele distributions between the observation group and the control group (χ² = 2.374, P > 0.05; χ² = 2.113, P > 0.05). Significant differences in CYP2E1 RsaI/PstI genotype and allele distributions between the two groups were observed (χ² = 9.129, P < 0.01; χ² = 6.028, P < 0.05).p><p>CONCLUSIONMutations at CYP2E1 RsaI/PstI can enhance the expression of CYP2E1 and this suggests individuals with the mutated gene have increased susceptibility to chronic benzene poisoning.p>
Alleles ; Benzene ; poisoning ; Cross-Sectional Studies ; Cytochrome P-450 CYP2E1 ; genetics ; metabolism ; Genetic Predisposition to Disease ; Genotype ; Humans ; Poisoning ; genetics ; Polymerase Chain Reaction ; Polymorphism, Genetic ; genetics ; Polymorphism, Restriction Fragment Length

<p>OBJECTIVETo assess the association of cytochrome P450 gene single nucleotide polymorphisms (SNPs) with susceptibility to gout in ethnic Han males from coastal regions of Shandong province.p><p>METHODSFour hundred and eighty male patients with gout and 480 healthy male controls were included. Genotyping was carried out with a custom Illumina GoldenGate Genotyping assay to detect SNP rs2275620 of CYP2C8 gene, SNP rs2070676 of CYP2E1 gene, SNP rs837395 of CYP4B1 gene, and SNP rs194150 of TBXAS1 gene. The association was assessed with chi-square test.p><p>RESULTSNo significant difference has been found between the two groups in regard to the genotypic and allelic frequencies of the TT, AT, AA genotypes and A, T alleles of the SNP rs2275620 of the CYP2C8 gene (P=0.88; P=0.97), the CC, CG, GG genotypes and C,G alleles of SNP rs2070676 of the CYP2E1 gene (P=0.24; P=0.09), the TT, AT, AA genotypes and A, T alleles of SNP rs837395 of the CYP4B1 (P=0.88; P=0.97), and TT, AT, AA genotypes and the A,T alleles of SNP rs194150 of TBXAS1 gene (P=0.15; P=0.06).p><p>CONCLUSIONThis study has identified no association of SNP loci rs2275620(A/T) of CYP2C8, rs2070676(C/G) of CYP2E1, rs837395(A/T) of CYP4B1 and rs194150(A/T) of TBXAS1 with gout in ethnic Han males from coastal regions in Shandong province. However, our result needs to be replicated in larger sets of patients collected from other regions and populations.p>
Adult ; Aryl Hydrocarbon Hydroxylases ; genetics ; Asian Continental Ancestry Group ; ethnology ; genetics ; China ; ethnology ; Cytochrome P-450 CYP2C8 ; genetics ; Cytochrome P-450 CYP2E1 ; genetics ; Disease Susceptibility ; Female ; Gout ; enzymology ; ethnology ; genetics ; Humans ; Male ; Middle Aged ; Polymorphism, Single Nucleotide ; Thromboxane-A Synthase ; genetics

Rats were continuously given different doses of water extract of Polygonum multiflorum (1, 10 g x kg(-1)) for 7 days to prepare liver microsomes. Cocktail in vitro incubation approach and Real-time quantitative PCR technology were used to observe the effect of water extract of P. multiflorum on CYP450 enzymatic activities and mRNA expressions in rat liver. Compared with the blank control group, both 1, 10 g x kg(-1) water extract of P. multiflorum treated groups showed significant inhibitions in CYP2E1 enzymatic activities and mRNA expressions (enzymatic activities of CYP2E1, P < 0.01; mRNA expression of CYP2E1, P < 0.05 in 1 g x kg(-1) group, P < 0.01 in 10 g x kg(-1) group). They revealed a significant increase in the enzymatic activity of CYP3A1 (P < 0.01), but without significant change in mRNA expressions. The 10 g x kg(-1) group showed a significant inhibition in CYP1A2 enzymatic activities and mRNA expressions in rat livers (P < 0.01).
Animals ; Cytochrome P-450 CYP1A2 ; genetics ; metabolism ; Cytochrome P-450 CYP2E1 ; genetics ; metabolism ; Cytochrome P-450 Enzyme Inhibitors ; administration & dosage ; isolation & purification ; Drugs, Chinese Herbal ; administration & dosage ; isolation & purification ; Liver ; drug effects ; enzymology ; Male ; Microsomes, Liver ; drug effects ; enzymology ; Polygonum ; chemistry ; RNA, Messenger ; genetics ; metabolism ; Rats ; Rats, Sprague-Dawley

<p>OBJECTIVETo investigate the effects of trichloroethylene (TCE) toxicity on the normal human liver cells (L02 cells) and hepatocytes with CYP2E1 gene overexpression which was constructed through molecular cloning technology in our laboratory, then to explore the roles of CYP2E1 gene in TCE toxicity.p><p>METHODSL02 cells and hepatocytes with CYP2E1 overexpression were treated with various doses of TCE (0,0.25, 0.5, 1.0, 2.0, 4.0 mmol/L) for 12h, the expression of apoptosis genes (Bcl-2, Caspase-3, Caspase-8, Caspase-9) and oncogenes (c-fos, c-myc, k-ras, p53) were determined by real-time fluorescent PCR.p><p>RESULTSBcl-2 mRNA expression levels increased significantly in normal liver cells and CYP2E1-overexpressing cells after TCE treatment, Bcl-2 levels were 20%∼50%higher in CYP2E1-overexpressing cells than in L02 liver cells at doses of 0.25∼2.0 mmol/L TCE. Caspase-3, Caspase-8 and caspase-9 mRNA expression increased by 30%∼600% in CYP2E1-overexpressing cells at doses of 0.5∼4.0 mmol/L TCE when compared with L02 cells (P < 0.01). Additionally, c-fos, k-ras and c-myc mRNA expression levels were 25%∼120% higher in CYP2E1-overexpressing cells than in L02 cells (P < 0.01), p53 mRNA expression levels were lower 10%∼50% in CYP2E1-overexpressing cells than in L02 cells (P < 0.05 or P < 0.01).p><p>CONCLUSIONSThere were significant differences for apoptosis gene and oncogene expression levels between normal liver cells and CYP2E1-overexpressing cells after they were treated with TCE, these findings indicated that CYP2E1 might play an important role in TCE metabolism in vivo.p>
Apoptosis Regulatory Proteins ; Caspase 3 ; Caspase 8 ; Caspase 9 ; Cytochrome P-450 CYP2E1 ; genetics ; Gene Expression ; Hepatocytes ; drug effects ; Humans ; Liver ; Proto-Oncogenes ; genetics ; RNA, Messenger ; Trichloroethylene ; toxicity

<p>OBJECTIVETo investigate the correlation of the polymorphisms of adiponectin receptor 2 (AdipoR2) gene +33371Gln/;Arg and cytochromes P4502E1 gene Rsa I (CYP2E1-Rsa I) as well as smoking with nonalcoholic fatty liver disease (NAFLD).p><p>METHODSThe polymorphisms of AdipoR2 gene +33371Gln/Arg and CYP2E1-Rsa I were analyzed with PCR technique in peripheral blood leukocytes from 750 NAFLD cases and 750 healthy subjects.p><p>RESULTSThe frequencies of AdipoR2 gene +33371Gln/Arg (A/A) and CYP2E1-Rsa I (c2/c2 ) were 39.20% and 71.73% in NAFLD cases, respectively, significantly higher than those in healthy subjects (21.07% and 43.07%, respectively, P<0.01). The risk of NAFLD increased significantly in subjects carrying +33371Gln/Arg (A/A) (OR=2.4156, 95% CI=1.8164-4.0725) and CYP2E1-Rsa I (c2/c2) (OR=3.3547, 95% CI=1.9182-4.5057). Combined analysis of the polymorphisms showed that the percentage of +33371Gln/Arg (A/A)/CYP2E1-Rsa I (c2/c2) was 32. 67% in NAFLD cases, significantly higher than that in the healthy subjects (6.40%, P<0.01), and subjects carrying both +33371Gln/Arg (A/A) and CYP2E1-Rsa I (c2/c2) had a high risk of NAFLD (OR=9.9264, 95% CI=4.2928-12.4241). The smoking rate was significantly higher in the case group than in the control group (OR=2.5919, 95% CI=1.4194-4. 9527, P<0.01), and statistical analysis suggested an interaction between smoking and +33371Gln/Arg (A/A)/CYP2E1-Rsa I (c2/c2) to increase the risk of NAFLD (OR=34.6764, 95% CI=18.9076-61.5825).p><p>CONCLUSION+33371Gln/Arg (A/A), CYP2E1-Rsa I (c2/c2 ) and smoking are risk factors for NAFLD and coordinately contribute to the occurrence of NAFLD.p>
Alleles ; Case-Control Studies ; Cytochrome P-450 CYP2E1 ; genetics ; Humans ; Non-alcoholic Fatty Liver Disease ; genetics ; Polymorphism, Genetic ; Receptors, Adiponectin ; genetics ; Risk Factors ; Smoking

<p>OBJECTIVETo prepare cytochrome (CYP)2E1-silenced hepatocytes by lentivirus-mediated RNA interference technology and to investigate the hepatotoxicity of trichloroethylene (TCE) in CYP2E1-silenced hepatocytes.p><p>METHODSShort hairpin RNA fragments were designed and synthesized and were then ligated into the lentiviral vector; single colonies were screened; the plasmid was extracted after PCR and sequence identification and then transferred into L02 hepatocytes; the CYP2E1-silenced hepatocytes were selected; real-time quantitative PCR and Western blot were used to evaluate the interference effects. The obtained CYP2E1-silenced hepatocytes, as well as normal L02 hepatocytes, were treated with TCE (0, 0.25, 0.50, 1.00, 2.00, and 4.00 mmol/L). The cell viability and half maximal inhibitory concentration (IC50) of TCE were measured; the apoptotic rate of cells was measured by flow cytometry; the mRNA expression levels of apoptosis genes and oncogenes were measured by real-time quantitative PCR.p><p>RESULTSThe IC50s of TCE for L02 hepatocytes and CYP2E1-silenced hepatocytes were 15.1 mmol/L and 23.6 mmol/L, respectively. The apoptotic rate increased as the dose of TCE rose in the two types of cells; the CYP2E1-silenced hepatocytes hada significantly lower apoptotic rate than L02 hepatocytes when they were exposed to 2.0 and 4.0 mmol/L TCE (P < 0.05 or P < 0.01). The mRNA expression level of bcl-2 (anti-apoptosis gene) in CYP2E1-silenced hepatocytes was 15% ∼ 60% higher than that in L02 hepatocytes (P < 0.01), while the mRNA expression levels of caspase-3 and caspase-9 (apoptosis genes) in CYP2E1-silenced hepatocytes were 30% ∼ 60% lower than those in L02 hepatocytes (P < 0.01). The mRNA expression level of p53 (cancer suppressor gene) in CYP2E1-silenced hepatocytes was 81 - 278% higher than that in L02 hepatocytes (P < 0.01), while the mRNA expression levels of c-fos and k-ras (oncogenes) in CYP2E1-silenced hepatocytes were 20-68% lower than those in L02 hepatocytes (P < 0.01).p><p>CONCLUSIONCYP2E1-silenced cells can be successfully prepared by lentivirus-mediated RNA interference technology. Silencing CYP2E1 gene can reduce the hepatotoxicity of TCE and inhibit the expression of some apoptosis genes and oncogenes, suggesting that CYP2E1 gene plays an important role in TCE metabolism and is related to the hepatotoxicity of TCE.p>
Apoptosis ; drug effects ; genetics ; Cell Line ; Cell Survival ; drug effects ; genetics ; Cytochrome P-450 CYP2E1 ; genetics ; metabolism ; Genetic Vectors ; Hepatocytes ; drug effects ; metabolism ; Humans ; Lentivirus ; genetics ; RNA Interference ; Trichloroethylene ; toxicity

Triptolide (TP) is a major active component in Tripterygium root, but its therapeutic window was very narrow due to its severe multi-organ toxicity. In this work, the effect of TP combined with glycyrrhetic acid (GA) on mRNA expression and activity of four cytochrome P450 (CYP) enzymes in rat liver was studied after intragastric administration of TP (0.05, 0.3 and 0.6 mg x kg(-1) x day(-1)) and TP (0.6 mg x kg(-1) x day(-1)) combined with GA (30 mg x kg(-1) x day(-1)) for 7 consecutive days. Compared with the control, the high dose of TP significantly up-regulated the mRNA expression levels of CYP2E1, 1A2, 3A1 and 2C11, the co-administration of TP and GA further up-regulated the mRNA expression levels of CYP3A1, 2C11 and 2E1 as compared with the high dose of TP. Meanwhile, TP at high dose and combined with GA significantly increased CYP3A-associated testosterone 6beta-hydroxylation activity (2.2-fold and 4.1-fold, respectively) as compared with the control. Because TP is mainly metabolized by CYP3A2 in male rats, the present work indicated that TP-induced increase of CYP3A activity might be an important reason for the rapidly metabolic clearance of TP in rat liver, and GA can reduce the hepatotoxicity of TP by promoting its hepatic metabolic clearance. Furthermore, the results also suggest that the drug interactions might be occurred when TP and GA were co-administered with other CYP3A substrate drug.
Animals ; Aryl Hydrocarbon Hydroxylases ; genetics ; metabolism ; Cytochrome P-450 CYP1A2 ; genetics ; metabolism ; Cytochrome P-450 CYP2E1 ; genetics ; metabolism ; Cytochrome P-450 CYP3A ; genetics ; metabolism ; Cytochrome P-450 Enzyme System ; genetics ; metabolism ; Cytochrome P450 Family 2 ; Diterpenes ; administration & dosage ; isolation & purification ; pharmacology ; Dose-Response Relationship, Drug ; Drug Combinations ; Drug Interactions ; Enzyme Activation ; Epoxy Compounds ; administration & dosage ; isolation & purification ; pharmacology ; Glycyrrhetinic Acid ; isolation & purification ; pharmacology ; Liver ; enzymology ; Male ; Phenanthrenes ; administration & dosage ; isolation & purification ; pharmacology ; Plant Roots ; chemistry ; Plants, Medicinal ; chemistry ; RNA, Messenger ; metabolism ; Rats ; Rats, Wistar ; Steroid 16-alpha-Hydroxylase ; genetics ; metabolism ; Tripterygium ; chemistry

Aged ; Carcinoma, Small Cell ; genetics ; Case-Control Studies ; Cytochrome P-450 CYP2E1 ; genetics ; Female ; Humans ; Lung Neoplasms ; genetics ; Male ; Middle Aged ; Polymorphism, Single Nucleotide