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)

The mixed-function oxidase system shows a number of variations in the liver of diethyl-nitrosamine (DEN) treated rats. These include a decrease of the cytochrome P450 content and of the aminopyrine demethylase activity both in the hyperplastic nodules and in the hepatoma. Processes of detoxification, such as the glutathione system, show some modifications. These alterations are in accordance with the decrease of glutathione peroxidase and the increase of gamma-glutamyltranspeptidase during diethyl-nitrosamine carcinogenesis.
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PMID:Functional alterations of the endoplasmic reticulum and the detoxification systems during diethyl-nitrosamine carcinogenesis in rat liver. 647 42

A cell line derived from a Morris hepatoma, MH1C1, was examined for its in vitro expression of monooxygenases. These cells were found to contain different forms of cytochrome P450, as shown by the response to inducers, namely phenobarbital (PB), 3-methylcholanthrene (MC) and metyrapone (MP). MH1C1 cell monolayers exposed to PB or MC showed an increase in the concentration of two spectrally distinct forms of cytochrome P450. The PB and MC treatments elicited enzyme activities towards the substrates aminopyrine and benzo(a)pyrene, respectively. The cell treatment with metyrapone led to a simultaneous stimulation of aminopyrine demethylase and benzo(a)pyrene hydroxylase activities, so underlining the peculiar features of this inducer.
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PMID:Induction of cytochrome(s) P450-dependent drug metabolism in cultured MH1C1 hepatoma cells. 651 25

We examined the induction of cytochrome P450-dependent mixed-function monooxygenase (MFO) in the human hepatoma cell line Hep G2 by means of several factors. The MFO activities induced in the cells cultured in medium containing five commercial sera varied significantly, and the activity in the cells cultured in the absence of serum was about twice as high as that in cells supplemented with serum. The activity of ethoxycoumarin O-deethylase was highest 12 hr after adding 3-methylcholanthrene, and it was induced by several polycyclic aromatic hydrocarbons such as benzo(a)anthracene and benzo(a)pyrene, which are usually found in urban air as environmental contaminants. Furthermore, an extract from the total suspended particles collected using a high volume air sampler, which was mutagenic in the Ames assay using Salmonella typhimurium TA98, induced the same enzyme activities in Hep G2 cells. These findings suggest that serum-free culture allows the stable and highly sensitive measurement of induced MFO activity, and that studies of MFO induction by environmental samples using human hepatoma Hep G2 cells should provide helpful information regarding the risk associated with environmental contaminants.
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PMID:Induction of cytochrome P450-dependent monooxygenase in serum-free cultured Hep G2 cells. 750 91

The aflatoxins are a group of closely related mycotoxins that are widely distributed in nature. The most important of the group is aflatoxin B1 (AFB1), which has a range of biological activities, including acute toxicity, teratogenicity, mutagenicity and carcinogenicity. In order for AFB1 to exert its effects, it must be converted to its reactive epoxide by the action of the mixed function mono-oxygenase enzyme systems (cytochrome P450-dependent) in the tissues (in particular, the liver) of the affected animal. This epoxide is highly reactive and can form derivatives with several cellular macromolecules, including DNA, RNA and protein. Cytochrome P450 enzymes may additionally catalyse the hydroxylation (to AFQ1 and AFM1) and demethylation (to AFP1) of the parent AFB1 molecule, resulting in products less toxic than AFB1. Conjugation of AFB1 to glutathione (mediated by glutathione S-transferase) and its subsequent excretion is regarded as an important detoxification pathway in animals. Resistance to AFB1 toxicity has been interpreted in terms of levels and activities of these detoxifying pathways. This article reviews the multiple reactions and effects attributed to aflatoxin, with particular reference to the interaction of aflatoxin with nucleic acids and proteins, and the contribution this mycotoxin has in disease development and in the promotion of hepatocellular carcinoma (HCC). The anti-mutagenic properties of several dietary factors are also considered in this article. Undoubtedly, the most important aspect of aflatoxin action is its putative role in the development of human cancer, in particular, HCC. Recently, there has been a renewed interest in this aspect and experimental evidence is rapidly accumulating at the molecular level, indicating aflatoxin as an important consideration in the aetiology of human HCC.
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PMID:Cellular interactions and metabolism of aflatoxin: an update. 754 Jul 67

The promutagenic and procarcinogenic heterocyclic amines (HAs) found in cooked meats are N-hydroxylated by microsomal cytochrome P450 enzymes as the first step in their metabolic activation. In cynomolgus monkeys, one of the HAs, 2-amino-3-methylimidazo[4,5-f]quinoline (IQ), has been shown to be a potent hepatocarcinogen. However, the structurally similar HA 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx) lacks this potency to induce hepatocellular carcinoma in monkeys. Liver microsomes from cynomolgus monkeys show a striking substrate specificity for the metabolic activation of IQ and MeIQx, the former being a far better substrate for N-hydroxylation. Western blot analysis showed that cynomolgus monkey hepatic microsomes constitutively express P450s immunologically related to the human CYP3A, CYP2C, and low levels of CYP1A1. For comparison, Western blot analysis of rat, human and patas monkey microsomes was also carried out. Treatment of cynomolgus monkeys with rifampicin induced hepatic cytochromes P450 related to human CYP3A4 and CYP2C9/10 without inducing CYP1A1 or CYP1A2. Immunoblot analysis also showed that chronic exposure of cynomolgus monkeys to IQ induced hepatic microsomal cytochrome CYP1A1 and CYP1A2, similarly but lesser in magnitude to that observed with 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCCD) induction. Using the Ames Salmonella mutagenicity assay, we examined the effect of the inducers on the mutagenic activation (i.e. N-hydroxylation) of IQ and MeIQx by cynomolgus monkey hepatic microsomes. We also examined the mutagenic activation of these HAs by rat, human and patas monkey liver microsomes. Microsomes from cynomolgus monkeys treated with rifampicin showed a 3-fold increase in the mutagenic activation of IQ but showed no increase in the mutagenic activation of MeIQx. Since cytochromes P4503A and/or P4502C are constitutively expressed in cynomolgus monkey hepatic microsomes, and upon induction with rifampicin are associated with an increased metabolic activation of IQ but not MeIQx, it appears that CYP3A and/or CYP2C are the isoform(s) showing the selective substrate specificity in the metabolic activation of IQ over MeIQx. Treatment of monkeys with TCDD significantly increased the mutagenic activation of both IQ and MeIQx, concomitant with an induction of CYP1A isozymes. Thus, it appears that TCDD-inducible CYP1A enzymes N-hydroxylate both substrates without selectivity. Together, these findings suggest that CYP3A and CYP2C are the principal isoforms in the cynomolgus monkey, associated with the metabolic activation implicated in the induction of hepatocarcinogenicity by IQ. Furthermore, the poor metabolic activation of MeIQx by CYP3A and CYP2C, coupled with low constitutive levels of CYP1A isozymes, provide a metabolic explanation for the low hepatocarcinogenic potency of MeIQx in cynomolgus monkeys.
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PMID:Cytochromes P450 in cynomolgus monkeys mutagenically activate 2-amino-3-methylimidazo[4,5-f]quinoline (IQ) but not 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx). 761 88

Normal human liver tissue and cultured human hepatocytes are valuable models to study xenobiotic metabolism and toxicity, but they only have a limited in vitro life-span and are not readily available. This report describes the establishment of replicative cultures of human adult liver epithelial cells in serum-free medium. The longevity of three of these cultures, derived from different donors, was extended by introduction of the simian virus 40 large T antigen gene. Two cell lines, THLE-2 and -3, established with a recombinant simian virus 40 large T antigen virus have undergone > 100 population doublings, are nontumorigenic when injected into athymic nude mice, have near-diploid karyotypes, and do not express alpha-fetoprotein. The cells express cytokeratin 18 and albumin in early passage, whereas higher-passage cells in logarithmic-phase growth also express cytokeratin 19. THLE-2 and -3 cells metabolize benzo[a]pyrene, N-nitrosodimethylamine, and aflatoxin B1 to their ultimate carcinogenic metabolites that adduct DNA, which indicates functional cytochrome P450 pathways. Other enzymes involved in metabolism of chemical carcinogens, such as epoxide hydrolase, NADPH cytochrome P450 reductase, superoxide dismutase, catalase, glutathione S-transferases, and glutathione peroxidase are also retained by THLE cells. Thus, these immortalized human liver cells constitute an in vitro model for pharmacotoxicological studies and for the investigation of etiology and pathogenesis of human hepatocellular carcinoma.
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PMID:Simian virus 40 large tumor antigen-immortalized normal human liver epithelial cells express hepatocyte characteristics and metabolize chemical carcinogens. 768 15

Acetaminophen (APAP) when administered in excess can cause severe hepatic necrosis in vivo. To study the mechanism of APAP toxicity and the role of cytochrome P450, a previously established human hepatoma HepG2 subline, MVh2E1-9, that constitutively expresses human CYP2E1 was used as a model. At high concentrations (above 5 mM) and when intracellular reduced glutathione (GSH) was depleted, APAP caused severe cytotoxicity in MVh2E1-9, but not in MV-5 cells which lack CYP2E1. The APAP cytotoxicity was dependent on the concentration of APAP and time of exposure, and could be blocked by 4-methylpyrazole, ethanol, diallyl sulfide, N-acetylcysteine and N-t-butyl-alpha-phenylnitrone, but not by propylgallate, an inhibitor of lipid peroxidation. Significantly more 14C-labeled APAP protein adduct was detected in MVh2E1-9 cells than MV-5 cells, especially after depletion of GSH. The formation of the APAP adducts could be inhibited by the same agents which prevent APAP cytotoxicity. At a lower concentration (1-2 mM), APAP inhibited proliferation in both MVh2E1-9 and the control MV-5 cells to similar extents. This antiproliferative action of APAP did not require depletion of GSH as did the cytotoxic action of APAP. These data suggest that APAP has a dual toxic effect on MVh2E1-9 cells: a P450-independent antiproliferative effect and the CYP2E1-dependent cytotoxic effect. These results demonstrate the ability of human CYP2E1 to activate APAP to reactive metabolites which form covalent protein adducts and cause toxicity to a hepatoma cell line.
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PMID:Cytotoxicity of acetaminophen in human cytochrome P4502E1-transfected HepG2 cells. 779 Nov 25

The mutagenicity, metabolism, DNA adduction and induction of unscheduled DNA synthesis (UDS) of 1-nitropyrene and 1,8-dinitropyrene were investigated in the human hepatoma cell line HepG2. Previous results had demonstrated that 1-nitropyrene was both mutagenic at the hgprt locus and induced UDS in these cells. In the present study, we find that the dinitropyrenes, although highly mutagenic in Salmonella typhimurium, are not mutagenic and do not induce UDS in the HepG2. Although the rate of 1,8-dinitropyrene nitroreduction was less than that of 1-nitropyrene nitroreduction, this did not explain the lack of mutagenicity and UDS induction by the dinitropyrenes. Therefore, it is proposed that the arylhydroxylamine O-esterificase is not expressed in these cells. Since cytochrome P450-mediated C-oxidation is the predominant metabolic pathway in vivo, we sought to determine if an increase in the ratio of cytochrome P450-mediated C-oxidation over nitroreduction would result in increased or decreased DNA adducts in the HepG2. The administration of 2.5 microM 3-methylcholanthrene to the HepG2 increased the ratio of C-oxidation/nitroreduction from 2.8 +/- 1.9 to 50.4 +/- 46.1. This was accompanied by a decrease in the C8-guanyl adduct of 1-nitropyrene (via nitroreduction) from 18.7 +/- 7.0 to 4.8 +/- 1.7 fmoles/micrograms DNA, without any further increase in other 1-nitropyrene DNA adducts. These results suggest that the cytochrome P450-mediated metabolism of 1-nitropyrene to epoxides, phenols, and dihydrodiols is not an activation pathway in the HepG2 cells, and may explain the weak carcinogenicity of 1-nitropyrene in vivo, where cytochrome P450-mediated C-oxidation predominates.
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PMID:Pathways for the mutagenesis of 1-nitropyrene and dinitropyrenes in the human hepatoma cell line HepG2. 788 47

Cytochrome P450 2C6 (CYP2C6) is a developmentally regulated, constitutively expressed form of rat liver microsomal cytochrome P450 that in the liver of adult male rats is induced to a limited extent by phenobarbital. The gene is not expressed at detectable levels in the lung, kidney, or brain. It is expressed and inducible by phenobarbital in differentiated Reuber hepatoma cells that express many hepatocyte-specific genes but not in dedifferentiated derivatives lacking the majority of hepatocyte-specific functions. A 505-base pair proximal segment of the CYP2C6 promoter is highly efficient in driving transcription of a linked chloramphenicol acetyltransferase reporter gene in the differentiated rat hepatoma cell line FGC4, is much less effective in a related dedifferentiated variant H5, and has no measurable activity in nonhepatic C33 human cervical carcinoma cells. The activity of the CYP2C6 promoter in the differentiated hepatoma cells is strongly dependent on hepatocyte nuclear factor (HNF)3, which acts at a complex site just upstream of the TATA motif. Transactivation experiments show that the D-site-binding protein (DBP) may also contribute to CYP2C6 promoter activity, via a site that is adjacent to the proximal HNF3 site. A substantial contribution to promoter activity by the base pair -505 to -316 segment is observed in FGC4 and H5 cells but not in HepG2 cells; deletion of this segment causes a marked diminution in promoter activity only in the former two cell lines. Although footprinting experiments have permitted the definition of three protein binding sites in this region (two HNF3 and one unidentified), mutation of these sites does not diminish promoter activity. The functionally important cis sequences in this region therefore remain to be defined. In HepG2 cells the distal region does not contribute to promoter activity. This most likely accounts for the low promoter activity in HepG2 and implies a deficiency in the relevant trans-acting factor(s).
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PMID:Hepatocyte nuclear factor 3 is a major determinant of CYP2C6 promoter activity in hepatoma cells. 805 60

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) induced cytochrome P450 IA1 activity in mouse primary hepatocyte cultures and mouse hepatoma Hepa-1 cells. Pretreatment with staurosporine, a protein kinase C inhibitor, inhibited TCDD-activated cytochrome P450 IA1 expression dose-dependently in both culture systems. Staurosporine also decreased P450IA1 protein synthesis which was detected using western immunoblot. Increased transcription of CYP1A1 gene by TCDD was also suppressed by staurosporine treatment. However, tyrphostin AG213, a specific tyrosine kinase inhibitor, had no effects on TCDD-induced cytochrome P450 expression. These results suggest that protein kinase C signal transduction may be involved in the cytochrome P450 induction mechanism by TCDD.
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PMID:Suppression of TCDD-induced cytochrome P450 IA1 activity by staurosporine in mouse primary hepatocyte cultures and hepatoma cells. 806 18


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