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)

Cytochrome P450 IA2, a liver-specific member of the 3-methylcholanthrene-inducible family, is never detected in established cell lines. With the aim of isolating cells stably producing this protein, we have used rat and mouse hepatoma cells as recipients in transfection experiments involving rabbit cytochrome P450 IA2 cDNA. We report here the isolation of five hepatoma cell clones expressing functional P450 IA2. The level of expression is comparable to that found in COS cells transiently transformed by other P450 cDNAs. It ranges between 0.4 and 1.6 pmol P450 IA2/mg total cell protein.
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PMID:Establishment of mouse and rat hepatoma cell clones showing stable expression of rabbit cytochrome P450 IA2. 259 5

An immunohistochemical technique was used to localize the major constitutive cytochrome P450 isozyme, P450 LM2, and the major beta-naphthoflavone-inducible isozyme, P450 LM4b, in the livers of untreated and aflatoxin B1 (AFB1)-initiated, tumor-bearing rainbow trout. In hepatic tissue sections from untreated trout, no regular anatomical pattern within the hepatic parenchymal cells could be discerned for either isozyme. Immunostaining was observed for P450 LM2 along the sinusoidal border of some of the parenchymal cells, there was moderate staining within the cytoplasm of most cells, and there were focal areas of increased staining. There was intense, uniform immunostaining for P450 LM2 within the cytoplasm of the bile duct cells, in the endothelial lining of arterioles, and along the epithelial surface of the gall bladder. Staining for P450 LM4b in livers from untreated trout was barely detectable. In liver tissue sections from AFB1-treated tumor-bearing fish, P450 LM2 appeared to be reduced and P450 LM4b was absent in the hepatocellular carcinoma nodules. An apparent increase in immunostaining for P450 LM4b was observed in nonneoplastic cells juxtaposed next to neoplastic cells as well as in areas distant to the tumors. These results may indicate that the pattern of P450 isozymes is altered in nonneoplastic cells of tumor-bearing trout livers.
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PMID:Cytochrome P450 isozyme distribution in normal and tumor-bearing hepatic tissue from rainbow trout (Salmo gairdneri). 265 90

A novel P450 cDNA, designated IVA3, was isolated from a lambda gt11 cDNA library from clofibrate-treated rat liver by screening with the lauric acid omega-hydroxylase, IVA1, cDNA probe. This cDNA encoded a protein with 507 amino acids and a calculated Mr of 58,239. The IVA3 cDNA shared 65% and 97% nucleotide and 72% and 96% DNA-deduced amino acid sequence similarities with IVA1 and IVA2, respectively. The CYP4A gene family, designated the Cyp4a locus, was mapped to mouse chromosome 4 using a panel of mouse-hamster somatic cell hybrids. Levels of the IVA mRNAs were analyzed in rat tissues and cell cultures after treatment with the hypolipidemic drug clofibrate. The IVA1, IVA2, and IVA3 mRNAs were present at very low levels in the livers of untreated rats and markedly induced in rats treated with clofibrate. Dose-response and time-course studies revealed that all three genes were regulated coordinately in liver. In contrast to the coordinate induction in liver, only the CYP4A3 gene was induced in the rat hepatoma cell line McA-RH7777. In the kidney, IVA1 and IVA3 mRNAs were present at low levels and were induced by clofibrate in a manner similar to that in liver. In contrast, the IVA2 mRNA was expressed in the kidney of untreated rats at a level similar to that of the maximally induced IVA2 mRNA in liver. These data indicate that the CYP4A1, CYP4A2, and CYP4A3 genes are regulated coordinately in liver while only CYP4A2 is activated constitutively in kidney.
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PMID:The rat clofibrate-inducible CYP4A subfamily. II. cDNA sequence of IVA3, mapping of the Cyp4a locus to mouse chromosome 4, and coordinate and tissue-specific regulation of the CYP4A genes. 276 33

The vaccinia virus cDNA expression system was used to produce human cytochrome P450 IA2 in a hepatoma cell line that is devoid of significant basal levels of P450. The expressed enzyme yielded a reduced carbon monoxide-bound difference spectrum with a lambda max of 449 nm. Catalytic activities and mutagen activation ability of the human enzyme were assessed and directly compared with results obtained with the orthologous mouse IA2, which was also expressed using vaccinia virus. Both the human and mouse enzymes were able to catalyze efficiently the p-hydroxylation of aniline. Mouse IA2 also catalyzed ethoxyresorufin O-deethylation, and its activity was sevenfold greater than expressed human IA2. The mouse and human enzymes also activated several promutagens and procarcinogens. Mouse IA2 was five- to sevenfold more active than the human enzyme for activation of the procarcinogens 2-acetylaminofluorene and benzo[a]pyrene-trans-7,8-dihydrodiol and the promutagens Glu-P-2 and Trp-P-1. Comparable activities were observed with 2-aminoanthracene, 2-aminofluorene, and Glu-P-1. These data demonstrate the utility of cDNA expression for examining the activities of human P450s and further suggest potentially important differences in catalytic activities of orthologous P450s found in different species.
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PMID:Human cDNA-expressed cytochrome P450 IA2: mutagen activation and substrate specificity. 280 20

The Long-Evans rat with a cinnamon-like coat color (LEC rat) is a mutant strain displaying hereditary hepatitis with severe jaundice. The age related difference in microsomal dealkylation of pentoxyresorufin and ethoxyresorufin was examined. The enzyme activity levels of pentoxyresorufin O-depentylase in LEC rats were decreased to 25% of the levels in control [Long-Evans rats with an agouti coat color (LEA rats)]. In contrast, ethoxyresorufin O-deethylase exhibited a much less marked difference between the strains. In parallel with these strain differences in enzyme activities, a decrease in phenobarbital (PB) inducible P450 isozymes, mainly P450b and P450e, was observed by Western blot analysis. The level of P450PB in LEC rats was more markedly depressed than in the LEA strain. On the other hand, microsomes from uninduced LEC rat liver had more 3-methylcholanthrene (MC) inducible P450MC, mainly P450c and P450d, than microsomes from LEA rat liver and these isozymes in the LEC were markedly induced by 3-methylcholanthrene treatment. The great difference in cytochrome P450PB content of the liver microsomes between LEC and LEA rats and the maintained constitutive levels of hepatic cytochrome P450MC in the LEC rats suggest a possible role of these cytochrome isozymes in the onset of spontaneous hepatitis and hepatoma.
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PMID:Selective expression and induction of cytochrome P450PB and P450MC during the development of hereditary hepatitis and hepatoma of LEC rats. 280 35

Ketoconazole, an imidazole derivative, is a member of a class of metabolic inhibitors acting specifically at cytochrome-P450 mediated reactions. We studied the effects of this compound on cholesterol synthesis, and on HMG-CoA reductase and LDL receptor activities, in cultures of human hepatoma cell line Hep G2. Ketoconazole, added in concentrations of 2-100 microM, inhibited cholesterol synthesis, and caused accumulation of lanosterol and dihydrolanosterol. Total mass formation of sterols was depressed. After 20 hr preincubation of the cells with the drug in these concentrations, activity of HMG-CoA reductase was markedly decreased, while the receptor-mediated binding, uptake and degradation of human LDL were increased. This increase is at least partly due to a higher affinity of LDL for its receptor. Ketoconazole prevented the fall in LDL-receptor activity caused by preincubation with LDL, whereas it did not affect the suppression caused by preincubation with exogenous mevalonate. These findings are discussed with respect to the involvement of endogenous sterol and non-sterol effectors of reductase and receptor activities.
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PMID:Effect of ketoconazole on cholesterol synthesis and on HMG-CoA reductase and LDL-receptor activities in Hep G2 cells. 303 62

We have developed a method to select for rat hepatoma cells that fail to express hepatocyte-specific functions. Well-differentiated cells descended from the H4IIEC3 hepatoma line express aldrin epoxidase (AE) activity, an indicator of the liver-specific forms of cytochromes P450 and, concurrently, are able to activate the procarcinogen aflatoxin B1 (AFB1) into highly toxic metabolites. Thus, differentiated hepatoma cells are highly sensitive to AFB1, while dedifferentiated derivatives, which fail to express AE activity, are resistant. Exposure of differentiated Fao cells to 10 microM AFB1 for 24 h permits the isolation, at a frequency of 5 x 10(-5), of resistant colonies that exhibit strongly reduced AE activity. Strikingly, various morphological types can be observed. In more than 90% of the colonies, cells are morphologically similar to the original differentiated cells and accumulate all liver-specific mRNAs examined in amounts comparable to Fao cells. Moreover, they are able to carry out gluconeogenesis, as judged by their capacity to grow in glucose-free medium. For a minor fraction of colonies, the cells exhibit nonhepatic morphology. These cells fail to express three or more of the liver functions and are not able to proliferate in glucose-free medium. Our results demonstrate that the use of AFB1 constitutes a simple and efficient single-step selective method for obtaining variant hepatoma cells of a wide variety of phenotypes.
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PMID:Efficient one-step selection of hepatoma cell variants of a variety of phenotypes by use of aflatoxin B1. 314 34

Hepatoma cells derived from the Reuber H35 rat hepatoma express cytochrome P450 enzymes of two major families: polycyclic aromatic hydrocarbon-inducible forms are found in both differentiated and dedifferentiated cells while phenobarbital (PB)-inducible forms are found only in differentiated cells. We report here that (i) benzanthracene and PB induce P450 c mRNA in differentiated and dedifferentiated cells and (ii) dexamethasone and PB induce P450 b/e and/or P450 PB1 mRNAs in differentiated cells but not in dedifferentiated cells.
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PMID:Phenobarbital, dexamethasone and benzanthracene induce several cytochrome P450 mRNAs in rat hepatoma cells. 338 91

A cell line derived from a human hepatoblastoma, HepG2, was examined for its ability to activate cyclophosphamide (CY) to a genotoxic form. Metabolism of CY to genotoxic product(s) was determined by the induction of sister-chromatid exchanges (SCE). The dose-dependent response pattern in HepG2 was compared to the patterns obtained by three other mammalian cell lines. HepG2 and a rat hepatoma cell line, H4-II-E, show similar dose-dependent increases of induced SCE, whereas non-hepatic-derived fibroblast lines show little or no CY-induced SCE. Microsomal enzyme activities characteristic of cytochromes P450 and P448 and epoxide hydrolase were examined in the two hepatoma cell lines and compared to levels in rat liver microsomal preparations. Although no cultured cell line can be a universal surrogate for in vivo metabolism, we propose that HepG2 may be useful to determine in a qualitative manner whether human cells possess the ability to activate a chemical to a genetically damaging form.
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PMID:Evaluation of a human hepatoma cell line as a target cell in genetic toxicology. 668 73

A human hepatocyte line (HHY41) was established from normal human liver tissue. This cell line was derived from a primary culture of human hepatocytes maintained between two layers of collagen gel for 4 weeks. It differs from other human hepatocyte lines in that transfection with the simian virus 40 gene was not used for cellular transformation and nonhepatocellular coculture cells were not present. HHY41 cells have proliferated freely in serum and hormone-supplemented medium after more than 1 year in continuous culture, exhibiting typical morphological characteristics of hepatocytes. HHY41 cells retain glucose-6-phosphatase activity. They also retain the ability to secrete liver-specific proteins such as albumin, transferrin, and alpha-fetoprotein. Northern blot analysis confirmed the presence of albumin mRNA. Cytochromes P450 induced by polycyclic aromatic hydrocarbons are maintained in these cells. Detection of cell surface antigens revealed that HHY41 cells express alpha 1 beta 1-integrin, which is expressed by normal hepatocytes and not by bile duct epithelial cells. High-molecular-weight cytokeratin, a marker for bile duct cells, is also absent in HHY41. Cytogenetic analysis showed hyperdiploid karyotype with a consistent deletion in the short arm of chromosome 1. HHY41 can be considered a new human hepatocyte line which retains liver-specific functions of differentiated hepatocytes. Derived from normal liver tissue, not a hepatocellular carcinoma, it provides a new model system for studying the regulation of cell growth and differentiated functions in human hepatocytes.
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PMID:Establishment of a human hepatocyte line derived from primary culture in a collagen gel sandwich culture system. 749 48


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