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)

Recent studies from this laboratory have demonstrated that L-tryptophan, after oxidation either by UV-irradiation or ozone, induces aryl hydrocarbon receptor (AhR) activation and binding of the liganded AhR complex to its specific DNA recognition site, thereby initiating transcription of the cytochrome P-450 1a1 (Cyp1a1) gene with concomitant increase of CYP1A1 protein and 7-ethoxyresorufin O-deethylase activity in wild-type mouse hepatoma cells, Hepa lclc7 (Hepa-1), in culture. Temporary inhibition of protein synthesis by cycloheximide resulted in superinduction of oxidized tryptophan-inducible CYP1A1 mRNA, protein, and 7-ethoxyresorufin O-deethylase activity in Hepa-1 cells. In the present communication, the results obtained by immunoblot analyses with monoclonal CYP1A1/1A2 antibody (NIH 1-7-1) demonstrate that both UV- or ozone-oxidized tryptophan also induce CYP1A2 protein in Hepa-1 cells. CYP1A2 mRNA, detected by reverse transcription-polymerase chain reaction, was markedly induced in the UV- or ozone-oxidized tryptophan-treated cells. Temporary inhibition of protein synthesis by cycloheximide further induced oxidized tryptophan-inducible CYP1A2 mRNA as well as the protein in Hepa-1 cells. This is the first report demonstrating the induction of CYP1A2 mRNA and protein in Hepa-1 cells.
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PMID:Induction of cytochrome P-450 1A2 by oxidized tryptophan in Hepa lclc7 cells. 1068 17

Green tea possesses significant anticancer activity in numerous experimental animal models, including demonstrated protection against aryl hydrocarbon induced cancers. The aryl hydrocarbon receptor (AhR) mediates the transcriptional activation of CYP1A1 and CYP1A2. In the present study, we investigated the effects of commercially available green tea extracts (GTEs) and individual tea catechins on the function of the AhR and on CYP1A gene expression in human hepatoma HepG2 cells and primary cultures of human hepatocytes. GTEs inhibited the transcription of a human CYP1A1 promoter-driven reporter gene induced by the AhR ligand 2,3,7, 8-tetrachlorodibenzo-p-dioxin (TCDD) in a concentration-dependent manner and inhibited the induced accumulation of both CYP1A1 and CYP1A2 mRNAs. GTEs blocked TCDD-induced binding of the AhR to DNA in HepG2 cells and in vitro in isolated hepatic cytosol. To determine if the observed effects were due to a single green tea component, we examined the four major catechins present in GTEs. Only (-)-epigallocatechin gallate (EGCG), the most abundant catechin in green tea, was able to inhibit TCDD-induced binding of the AhR to DNA and subsequent CYP1A transcription, however EGCG alone was less effective than GTEs. We next examined GTEs and catechins for AhR agonist activity. GTEs caused a concentration-dependent increase in CYP1A1-promoter driven reporter gene activity and caused accumulation of CYP1A1 mRNA and protein, but we found that individual catechins were unable to induce the expression of CYP1A1. Our results demonstrate that GTEs as a whole exert mixed agonist/antagonist activity on the AhR, while EGCG functions as a strict AhR antagonist. Therefore, modulation of human CYP1A expression by green tea extracts can not be attributed to the action of a single tea catechin, but rather is due to the effects of a complex mixture. These findings may be useful in future studies concerning green tea as a cancer preventive agent.
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PMID:Comparative studies on the effects of green tea extracts and individual tea catechins on human CYP1A gene expression. 1106 4

The Ah receptor mediates the induction of cytochrome P450 1A1 (CYP1A1) and toxicities of 2,3,7,8tetrachlorodibanzo-p-dioxin (TCDD). It has been detected in tissues of many species and in murine and human hepatoma lines. We show that the human hepatoma line SK-Hep-1 has cytosolic Ah receptor detectable by specific binding of [3H]TCDD. Concentrations of Ah receptor were low (mean = 43 +/- 3 fmol/mg cytosol protein compared to 430 fmol/mg protein in Hepa-1); the estimated number of receptor sites per cell is approximately 9,000, compared to 35,000 in Hepa-1. Ah receptor in SK-Hep-1 cells was physicochemically similar to Ah receptor in C57BL/6 mouse liver and in other human hepatoma lines studied to date except that binding affinity for TCDD, the most avidly bound ligand, was lower (estimated Kd was 14 nM by Woolf plot analysis). Translocation of the Ah receptor-ligand complex to the nucleus was shown; binding of the activated Ah receptor-ligand complex to an XRE in the 5'-upstream region of the CYP1A1 gene was demonstrated by gel-shift analysis. However, after SK-Hep-1 cells were incubated with typical PAHs including 3-methylcholanthrene, benzanthracene, and dibenz(a,h)anthracene, each over a wide range of concentrations, no induction of aryl hydrocarbon hydroxylase activity was detectable. On Northern analysis, no message for human CYP1A1 was detected in mRNA prepared from noninduced SK-Hep-1 cells or from cells treated for 24 h with 13 microM dibenz(a,h)anthracene. Further analysis by RT-PCR did not detect the induction of CYP1A1, CYP1A2, or CYP1B1 message in response to 10(-7) M TCDD, 10(-5) M benzanthracene, or 10(-5) M 3-methylcholanthrene. Transient transfection of reporter constructs containing either a minimal promoter or the CYP1A1 promoter fused to a reporter gene (luciferase) did not show any expression in response to increasing concentrations of TCDD up to 10(-8) M. Estimation of the size of the transcripts for AhR and ARNT protein revealed normal sizes, 2.7 and 2.4 kb, respectively. Together, these data suggest that SK-Hep-1 cells express an Ah receptor defective at the level of trans-activation of gene expression. SK-Hep-1 is the first human hepatoma line described with a demonstrable defect in CYP1A1 or its regulation.
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PMID:Failure of Ah receptor to mediate induction of cytochromes P450 in the CYP1 family in the human hepatoma line SK-Hep-1. 1114 30

Either G-2964 or A734 in the human CYP1A2 gene was confirmed to be associated with high inducible enzyme activity in smokers, but not in nonsmokers. In this study, for the first time, we observed an association between phenotypes and genotypes of CYP1A2 with respect to the two genetic polymorphisms in 163 healthy Chinese volunteers living in Qidong. The ratio of plasma 17X/137X at 6 h after oral administration of 300 mg caffeine was employed in CYP1A2 phenotyping analysis, while genotyping analysis was carried out by polymerase chain reaction-restriction fragment length polymorphism. The allele frequencies of A at -2964 and A at 734 in 139 non-smoking subjects were 0.25 and 0.67, respectively. The A/A-2964C/C734, G/A-2964C/C734 or A/A-2964C/A734 genotype that was thought to have lower inducibility/activity of CYP1A2 than the other genotypes did not exist in the tested Chinese subjects. The ratio of 17X/137X was 0.46 +/- 0.26 in G/G-2964A/A734 genotypes (n = 22) and 0.36 +/- 0.19 in non-G/G-2964A/A734 (n = 117). In addition, there was significant difference between them (P = 0.036). A similar result was also achieved in 24 smokers. Since Qidong is a special region with particularly high incidence of hepatocellular carcinoma in China, the association of phenotypes with genotypes of CYP1A2 in the Qidong population might result from some inducible environmental factors such as those of cigarettes in smokers.
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PMID:Plasma caffeine metabolite ratio (17X/137X) in vivo associated with G-2964A and C734A polymorphisms of human CYP1A2. 1147 Sep 95

Allyl sulfides such as diallyl sulfide (DAS), diallyl disulfide (DADS), and diallyl trisulfide (DATS), typical flavor components of Allium vegetables, have been shown to inhibit benzo[a]pyrene (B[a]P)-induced carcinogenesis in animal models. As a possible mechanism of this inhibition, the effect of these volatile substances on cytochrome P450 (CYP)1 (CYP1A1, 1A2 and 1B1)-mediated bioactivation of B[a]P was investigated using a human hepatoma cell model (HepG2). DADS and DATS inhibited the B[a]P-induced ethoxyresorufin O-deethylase (EROD) activity, a marker enzyme for CYP1, by 30-90% and 70-95% at 100-1,000 microM concentration, respectively. The cell viability, an indicator of the capacity to inhibit B[a]P bioactivation, was increased by treatments of 100-1,000 microM DADS and 10-100 microM DATS. Immunoblot results indicated that the B[a]P inducible CYP1A2 protein was suppressed by 100-1,000 microM of DADS and 10-100 microM of DATS, but CYP1A1 and 1B1 were not detectable in any microsomes. Analysis of B[a]P metabolites revealed that the level of 7,8-diol formed was significantly reduced in the DADS and DATS treated microsomes as compared to the control. The level of 9,10-diol and 4,5-diol formed was also lowered by the allyl sulfide treatments. These results suggest that the protective mechanism of allyl sulfides on B[a]P-induced carcinogenesis is possibly related with the modulation of CYP1-mediated bioactivation of B[a]P.
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PMID:Modulation of cytochrome P4501-mediated bioactivation of benzo[a]pyrene by volatile allyl sulfides in human hepatoma cells. 1175 11

Nitropolycyclic aromatic hydrocarbons (NPAHs) are found in diesel exhaust and ambient air. NPAHs as well as polycyclic aromatic hydrocarbons (PAHs) are known to have mutagenicity, carcinogenicity, and endocrine-disruptive effects. In the present study, the inducibility of the human cytochrome P450-1 (CYP1) family by NPAHs was compared with those produced by their parent PAHs and some reductive metabolites, amino-PAHs. Furthermore, to investigate the differences in the inducibility of the CYP1 family in human tissues, various human tissue-derived cell lines, namely HepG2 (hepatocellular carcinoma), ACHN (renal carcinoma), A549 (lung carcinoma), MCF-7 (breast carcinoma), LS-180 (colon carcinoma), HT-1197 (bladder carcinoma), HeLa (cervix of uterus adenocarcinoma), OMC-3 (ovarian carcinoma), and NEC14 (testis embryonal carcinoma), were treated with NPAHs, PAHs, or amino-PAHs. The mRNA levels of CYP1A1, CYP1A2, and CYP1B1 were determined with reverse transcription-polymerase chain reaction (RT-PCR). The cell lines were classified into two groups: CYP1 inducible cell lines, comprising HepG2, MCF-7, LS-180, and OMC-3 cells, and CYP1 non-inducible cell lines, comprising ACHN, A549, HT-1197, HeLa, and NEC14 cells. In inducible cell lines, the induction profile of chemical specificity was similar for CYP1A1, CYP1A2, and CYP1B1, although the extent of induction differed among the cell lines and for the CYP isoforms. Pyrene, 1-nitropyrene, 1-aminopyrene, 1,3-, 1,6-, and 1,8-dinitropyrenes slightly induced CYP1 mRNAs, but 1,3-dinitropyrene produced a 6-fold induction of CYP1A1 mRNA in MCF-7 cells. 2-Nitrofluoranthene and 3-nitrofluoranthene exhibited stronger inducibility than fluoranthene in the inducible cell lines. 6-Nitrochrysene induced CYP1 mRNAs to the same extent or more potently than chrysene. The induction potencies of 6-nitrobenzo[ a]pyrene and 7-nitrobenz[ a]anthracene were weaker than those of their parents benzo[ a]pyrene and benz[ a]anthracene, respectively. This study demonstrated that NPAHs as well as PAHs induced human CYP1A1, CYP1A2, and CYP1B1 in a chemical-, CYP isoform-, and cell-specific manner. Furthermore, the cell-specific induction of the CYP1 family was not related to the expression levels of aryl hydrocarbon receptor, aryl hydrocarbon nuclear translocator, or estrogen receptors alpha and beta.
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PMID:Induction of CYP1A1, CYP1A2, and CYP1B1 mRNAs by nitropolycyclic aromatic hydrocarbons in various human tissue-derived cells: chemical-, cytochrome P450 isoform-, and cell-specific differences. 1210 46

DNA microarrays and real time PCR were used to analyze the mechanism of gene induction by CYP1A1 inducers, beta-naphthoflavone, and omeprazole, in the human hepatocellular carcinoma HepG2 cells. Reproducible and significant inductions were observed in a limited number of genes including CYP1A1 and CYP1A2. Genes induced by omeprazole included several protein tyrosine kinase targets. This result confirmed that omeprazole could modulate gene expressions through protein tyrosine kinase-mediated pathway. Induction ratios were considerably different from CYP1A1 and CYP1A2 (>10-fold) to other induced genes (<5-fold). alpha-Naphthoflavone, which is known as an antagonist to 2,3,7,8-tetrachlorodibenzo-p-dioxin, inhibited the inductions of heme oxygenase 1, glutamate-cysteine ligase (modifier unit), and thioredoxin reductase by beta-naphthoflavone but not those of CYP1A1 and CYP1A2. It unexpectedly enhanced the beta-naphthoflavone-mediated CYP1A1 and CYP1A2 induction. These results suggest that the CYP1A1 and CYP1A2 genes, which share their 5(') enhancer regions, are regulated differently from the other genes.
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PMID:Characterization of human CYP1A1/1A2 induction by DNA microarray and alpha-naphthoflavone. 1214 46

In experimental animals, CYP1A2 is absolutely required for the development of uroporphyria induced by treatment with polyhalogenated aromatic compounds or other compounds. Although the role of this CYP in clinical uroporphyria, porphyria cutanea tarda (PCT), is not clear, Cyp1a2(-/-) mice are resistant to the development of uroporphyria. Here, we compared the abilities of human and mouse CYP1A2 expressed in mouse hepatoma Hepa-1 cells to: (i) catalyze CYP1A2-dependent methoxyresorufin demethylase (MROD), and (ii) support uroporphyrin (URO) accumulation. Both CYP1A2 orthologs were expressed at similar levels as indicated by immunodetectable CYP1A2 proteins and MROD activities. URO accumulation was increased in cultures expressing either ortholog when supplemented with 5-aminolevulinic acid, the porphyrin precursor. Cells expressing mouse CYP1A2 produced more URO than cells expressing human CYP1A2. The results indicate that human CYP1A2 can support URO accumulation in hepatoma cells and thus may play a role in human PCT.
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PMID:Uroporphyrin accumulation in hepatoma cells expressing human or mouse CYP1A2: relation to the role of CYP1A2 in human porphyria cutanea tarda. 1256 81

Cancer risk can be influenced by the exposure to endogenous or environmental toxins. Polymorphic enzymes involved in the metabolic activation/detoxification of carcinogens may account for individual variations of risk. We studied the polymorphisms of five enzymes of the P450 superfamily, CYP1A1, CYP1A2, CYP2D6, CYP2E1 and CY3A4, as risk factors for liver disease progression and cancer in hepatitis C virus-infected patients. CYP genotyping was performed by polymerase chain reaction (PCR) restriction fragment length polymorphism or allele-specific PCR. Different stages of disease were considered, as follows: 90 asymptomatic carriers and 87 chronic hepatitis, 92 cirrhosis and 91 hepatocellular carcinoma (HCC) cases. Reference allele frequencies were obtained from 99 blood donors. Allele distributions among categories were compared using the chi(2) test. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated to express relative risks. Independent associations were modeled by correspondence analysis and logistic regression. Frequencies of the CYP1A1 highly inducible alleles, MspI m2 and Val, were increased in liver disease patients compared with carriers; no specific association with HCC was found. The high-activity CYP2E1 c2 allele was underrepresented among HCC patients with respect to other HCV categories, including cirrhosis. CYP2D6 poor metabolizer (PM) genotypes were significantly more frequent in healthy subjects (7.1%) and carriers (11.1%) than in hepatitis/cirrhosis (4.6%) and HCC (1.2%) patients. This was confirmed by multivariable analysis. PM genotypes protected against progressive disease as ORs reduced proportionally to stage. The age at diagnosis for HCC was anticipated in non-PM individuals. No differences were seen for CYP1A2 and CYP3A4 genes. Polymorphic variants of CYP genes may contribute to the progression of liver disease and HCC risk in HCV-infected subjects.
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PMID:CYP enzyme polymorphisms and susceptibility to HCV-related chronic liver disease and liver cancer. 1256 54

1. Xenobiotic-mediated regulation of mRNA expression of all members of the human cytochrome P450 (CYP) 1 family has been measured by RT-PCR in the hepatoma cell line, HepG2. Besides the positive control beta -naphthoflavone, the H(+)/K(+)-ATPase inhibitors omeprazole, lansoprazole, pantoprazole and rabeprazole and the anti-malaria drug primaquine were included in this study. 2. beta-Naphthoflavone, primaquine, omeprazole and lansoprazole increased mRNA levels of CYP1A1, CYP1A2 and CYP1B1. Induction by rabeprazole was significant only for CYP1A1 and CYP1A2, whereas none of the CYP1 mRNAs was induced by pantoprazole. This result was confirmed in primary human hepatocytes. 3. Transcriptional regulation was proved by inhibition of induction with actinomycin D. 4. Increase of CYP1 mRNA was significant after 1 h and maximal after 4 h. CYP1B1, but not CYP1A1 or CYP1A2, was dramatically down-regulated between 4 and 24 h. This decrease was prevented by treatment of cells with actinomycin D after induction, indicating an active transcription-dependent mechanism of CYP1B1 mRNA degradation. 5. In conclusion, xenobiotics inducing CYP1A1 mRNA expression have been shown also to induce CYP1A2 and CYP1B1, differing only with regard to level and time course of induction.
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PMID:Time-dependent transcriptional induction of CYP1A1, CYP1A2 and CYP1B1 mRNAs by H+/K+ -ATPase inhibitors and other xenobiotics. 1262 54


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