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)

Lipid peroxidation is often low in tumor tissue as compared to the corresponding normal tissue and it has been postulated that lipid peroxidation may be associated with cell division. In this paper the various contributory factors which control the rate of microsomal lipid peroxidation in normal rat liver and in the Novikoff hepatoma have been carefully analyzed. The low rate of lipid peroxidation in the hepatoma seems to be due to a combination of factors: low levels of polyunsaturated fatty acids and of cytochrome P-450 and elevated levels of lipid-soluble antioxidant. This lipid-soluble antioxidant is principally alpha-tocopherol.
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PMID:Lipid peroxidation and lipid antioxidants in normal and tumor cells. 651 77

Four ethylated derivatives of fluorescein were synthesized and their metabolism by mouse liver homogenates and cultured mouse hepatoma cells was investigated. Two of the ethylfluoresceins are specifically metabolized by the polycyclic aromatic hydrocarbon inducible cytochrome P-450 to yield fluorescein, which is about 15 times more fluorescent than the ethylated compounds. One of these fluorogenic derivatives, ethoxyfluorescein ethyl ester, is useful for flow cytometric analysis and sorting of intact, viable cells on the basis of cytochrome P-450 activity. The structure-activity relationship of the ethylfluoresceins is discussed.
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PMID:Ethylated fluoresceins: assay of cytochrome P-450 activity and application to measurements in single cells by flow cytometry. 663 86

Hydroxyurea induces DNA repair replication in the cytochrome P-450-containing C2Rev7 rat hepatoma cell line. Repair is severalfold increased by pretreatment of the cells with dexamethasone, which induces cytochrome P-450-dependent monooxygenase activities in these cells. In the dedifferentiated hepatoma line H5, which strongly expresses cytochrome P-448 but no cytochrome P-450-dependent enzyme activities, hydroxyurea is not genotoxic. The results support the notion that the formation of genotoxic metabolites from hydroxyurea is mediated by a cytochrome P-450-dependent enzyme.
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PMID:Evidence for the involvement of cytochrome P-450-dependent monooxygenase(s) in the formation of genotoxic metabolites from N-hydroxyurea. 670 84

4'-Iodo-, 4'-bromo-, 4'-chloro- and 4'-fluoro-2,3,4,5-tetrachlorobiphenyl were administered to immature male Wistar rats and the effects of this homologous series of 4'-halo-2,3,4,5-tetrachlorobiphenyls on the microsomal drug-metabolizing enzymes were determined. All the halogenated biphenyls increased microsomal benzo[a]pyrene hydroxylase (or aryl hydrocarbon hydroxylase, AHH), ethoxyresorufin (ER) O-deethylase and dimethylaminoantipyrine (DMAP) N-demethylase. The effects of the 4'-halo-2,3,4,5-tetrachlorobiphenyls on the microsomal enzyme activities and on the relative peak intensities and spectral shifts of the reduced cytochrome P-450:CO and ethylisocyanide (EIC) binding difference spectra were similar to those observed after coadministration of phenobarbitone (PB) and 3-methylcholanthrene (MC). The relative activities of the halogenated biphenyls were determined using two in vitro assays; namely cytochrome P-448 associated induction in rat hepatoma H-4-II E cells in culture and competitive binding to the hepatic cytosolic Ah receptor protein from male Wistar rats. Dose-response experiments for the iodo, bromo, chloro and fluoro analogs gave EC50(M) values of 8.5 x 10(-9), 6.6 x 10(-8), 5.7 x 10(-7), and 3.3 x 10(-5), and 1.5 x 10(-6), 2.5 x 10(-6), 4.1 x 10(-6) and 2.5 x 10(-5) for the Er O-deethylase induction and receptor binding assays respectively. The relative potencies of the 4'-halo-2,3,4,5-tetrachlorobiphenyls followed the order I greater than Br greater than Cl greater than F for both assays and differences in the EC50 values for the iodo and fluoro analogs were greater than three orders of magnitude for ER O-deethylase induction in rat hepatoma cells in culture. One possible explanation for these effects may be associated with differences in the polarizability of the laterally substituted halogen groups. However, other differences in the physico-chemical properties of the halogen atoms may also be important.
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PMID:Halogenated biphenyls as AHH inducers: effects of different halogen substituents. 713 65

Incubation of leukotriene B4 (LTB4) with Hep G2 cells (a human-derived hepatoma cell line) resulted in the production of several metabolites indicative of alternative pathways of LTB4 metabolism not previously observed in normal hepatocytes. The major extracellular LTB4-derived metabolites were structurally identified using mass spectrometry and ancillary techniques including electrospray ionization. The major metabolite was 10-hydroxy-4,6,8,12-octadecatetraenoic acid (10-HOTE), an unexpected metabolite which lost the hydroxy group at carbon 5 from the parent LTB4. Two other major metabolites were 3(R)-hydroxy-LTB4 and 3(S)-hydroxy-LTB4. The formation of these three metabolites revealed that beta-oxidation from the carboxyl terminus can be a significant metabolic pathway for degradation of this hydroxy unsaturated fatty acid. The normal hepatocyte LTB4-derived metabolite, 20-carboxy-LTB4, was observed as only a minor product. The metabolic profile for Hep G2 cells suggests that the efficient cytochrome P-450 pathway involved in omega-oxidation in typical hepatocytes is absent in these cells. Several minor metabolites were also identified which included dihydro products resulting from metabolism by a 12-hydroxydehydrogenase/delta 10-reductase pathway. The formation of the major metabolite reveals the operation of steps in beta-oxidation of hydroxy, unsaturated fatty acids not anticipated by previously identified steps of fatty acid beta-oxidation.
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PMID:Metabolism of leukotriene B4 in cultured hepatoma cells. 764 63

Conditions have been established for H4IIE rat hepatoma cell cultures in which effects of cytochrome P-450 induction on the metabolism of a munitions wastestream pollutant can be studied. Under these conditions, the polychlorinated hydrocarbon 2,3,4,7,8-pentachlorodibenzfuran (PCDBF) induced cytochrome P-450 (1A1) aryl hydrocarbon hydroxylase (AHH) activity over a wide range of concentrations without significant cytotoxic effects. The munition pollutant 2,4-dinitrotoluene (2,4-DNT) did not induce AHH activity itself, but its metabolism was considerably altered when applied to PCDBF induced cultures. Production of amino nitrotoluene isomers was greatly enhanced in induced cultures as compared to uninduced controls, as was the conversion of radiolabeled 2,4-DNT to relatively more polar metabolites. To some extent, the results with H4IIE cells parallel those reported for animals exposed to 2,4-DNT after induction of cytochrome P-450 AHH activity. The preliminary findings suggest that with further development and validation, H4IIE cultures could be of use in characterizing metabolites that result from exposure to chemical mixtures involving a P-450 (1A1) inducer.
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PMID:Nitroreduction of 2,4-dinitrotoluene in vitro by cytochrome P-450 induced H4IIE cells. 766 53

A full-length cDNA for the human liver mitochondrial cytochrome P-450 CYP27 was cloned from a human hepatoma HepG2 cDNA library and then subcloned into the mammalian expression vector pSG5. When CYP27 cDNA was transfected into COS-1 transformed monkey kidney cells along with adrenodoxin cDNA, transfected cells revealed a 10- to 20-fold higher vitamin D3-25-hydroxylase activity than nontransfected cells. Transfected cells were capable of 25-hydroxylation of vitamin D3, 1 alpha-hydroxyvitamin D3 and 1 alpha-hydroxydihydrotachysterol3. In each case they also showed the ability to 26(27)-hydroxylate the cholesterol-like (D3) side chain. The relative rates of 25- and 26(27)-hydroxylation of 1 alpha-hydroxyvitamin D3 approximately mimicked the ratio of products observed in HepG2 cells. Vitamin D2 and 1 alpha-hydroxyvitamin D2, both with the ergosterol-like side chain, were 24- and 26(27)-hydroxylated by CYP27. The rate of side-chain 24-, 25-, or 26(27)-hydroxylation was greater for 1 alpha-hydroxylated vitamin D analogs than for their nonhydroxylated counterparts. We conclude that CYP27 is capable of 24-, 25-, and 26(27)-hydroxylation of vitamin D analogs and that the nature of products is partially dictated by the side chain of the substrate. This work has revealed that the cytochrome P-450 CYP27 may be important in the metabolism of vitamin D analogs used as drugs.
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PMID:Transfected human liver cytochrome P-450 hydroxylates vitamin D analogs at different side-chain positions. 769 Sep 68

The supernatant from human Hep G2 hepatoma cells was examined for typical enzymatic activities involved in the metabolism of xenobiotics. Neither cytochrome P-450 nor b5 was detectable, but associated enzymatic activities were found especially after induction with hydrocortisone (HC) and benzanthracene (BA) suggesting that this Hep G2 supernatant contains cyt P-450 IA1 and IA2. Other critical enzymes are also present, but, as expected, at lower activities than in Aroclor 1254 rat liver S9, except for NADH and NADPH cytochrome c reductase. Results of the Ames test indicate that the induced Hep G2 supernatant is a suitable activator for the evaluation of genotoxicity of indirect mutagens.
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PMID:Metabolic activation by a supernatant from human hepatoma cells: a possible alternative in mutagenic tests. 769 57

Mammalian organisms possess a variety of enzymes that catalyze the biotransformation of numerous chemicals with diverse structure. The gene superfamily comprising the cytochrome P-450 monooxygenases (P-450) are key participants in these reactions, and certain P-450 genes are highly inducible upon xenobiotic exposure. Many of the standard techniques used in the study of these systems rely on the disruption of tissues and cells, together with the preparation of subcellular particles. We have adopted a sensitive new technique, scanning laser cytometry, to monitor P-450-mediated O-dealkylation activities directly in cultured cells. Metabolism in single cells was quantified by fluorescence detection of resorufin, the P-450-mediated O-dealkylation product of alkoxyresorufin ether substrate probes. Functional activities associated with P-4501A1 and NADPH DT-diaphorase were compared among a human hepatoma (Hep G2) cell line and cells derived from mouse (Hepa 1clc7 wt) and rat (H4-II-E) hepatomas. Pretreating cells with the polyaromatic hydrocarbon inducer beta-naphthoflavone resulted in 50- to 100-fold increases in single cell rates of O-dealkylation of ethoxyresorufin (EROD activity). The use of scanning laser cytometry enabled in situ analysis of both constitutive and inducible biotransformation activities without disruption of cells or intracellular processes that determine the toxicologic fate of exogenous chemicals in vivo.
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PMID:Direct determination of functional activity of cytochrome P-4501A1 and NADPH DT-diaphorase in hepatoma cell lines using noninvasive scanning laser cytometry. 769 59

We studied the effect of piperine on the cytotoxicity and genotoxicity of aflatoxin B1 (AFB1) in rat hepatoma cells H4IIEC3/G-(H4IIE) using cellular growth and formation of micronuclei as endpoints. Piperine was earlier shown to inhibit cytochrome P-450-dependent aryl hydrocarbon hydroxylase and 7-methoxycoumarin demethylase activities in preparations of these cells with 1/2 maximum inhibition at 30-50 microM (Singh J. and Reen R.K., Current Science, 66, 365-369, 1994). The results of the present study showed that AFB1 inhibited the growth of H4IIE cells with an ED50 of 15 nM. Piperine markedly reduced the toxicity of the mycotoxin. Thus at 100 microM piperine largely restored the rate of growth of the cells. Likewise, piperine reduced the AFB1-induced formation of micronuclei in a concentration-dependent manner. Piperine itself was not toxic to the cells up to a concentration of almost 100 microM. The results suggest, that piperine is capable of counteracting AFB1 toxicity by suppressing cytochromes P-450 mediated bioactivation of the mycotoxin.
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PMID:Piperine, a major ingredient of black and long peppers, protects against AFB1-induced cytotoxicity and micronuclei formation in H4IIEC3 rat hepatoma cells. 798 7


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