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 cytotoxic properties of quinone drugs such as menadione and adriamycin are thought to be mediated through one-electron reduction to semiquinone free radicals. Redox cycling of the semiquinones results in the generation of reactive oxygen species and in oxidative damage. In this study the toxicity of mitozantrone, a novel quinone anticancer drug, was compared with that of menadione in human Hep G2 hepatoma cells. Mitozantrone toxicity in these cells was not mediated by the one-electron reduction pathway. In support of this, inhibition of the enzymes glutathione reductase and catalase, responsible for protecting the cells from oxidative damage, did not affect the response of the Hep G2 cells to mitozantrone, whereas it exacerbated menadione toxicity. In addition, the toxicity of menadione was preceded by depletion of reduced glutathione which was probably due to oxidation of the glutathione. Mitozantrone did not cause glutathione depletion prior to cell death. DT-diaphorase activity and intracellular glutathione were found to protect the cells from the toxicity of both quinones. Inhibition of epoxide hydrolase potentiated mitozantrone toxicity but did not affect that of menadione. Our experiments indicate that mitozantrone toxicity may involve activation to an epoxide intermediate. Both quinone drugs inhibited cytochrome P-450-dependent mixed-function oxidase activity, although menadione was more potent in this respect.
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PMID:The toxicity of menadione and mitozantrone in human liver-derived Hep G2 hepatoma cells. 253 22

The tissues of hepatocellular carcinoma were operatively resected from six patients. All four components of the systems of microsomal cytochrome P-450-linked monooxygenase of the tissues were investigated and compared to those of normal liver tissue. The concentrations of cytochromes P-450, P-420 and b5 were measured optically and the concentrations of all components except cytochrome P-450 were measured by the Western blotting method followed by immunochemical staining. In microsomes of hepatocellular carcinoma tissues, there was as much cytochrome P-450 and other redox components as in the normal liver tissues, but cytochrome P-450 in liver cancer tissues was unstable and easily converted to cytochrome P-420. The specific activities of NADPH- and NADH-ferricyanide and cytochrome c reductase of each sample were also measured. In the microsomes of the cancer tissues, the specific activities were remarkably reduced compared with those of normal liver tissues. The lipid compositions of the microsomes and the phospholipid/cholesterol ratios (w/w) were 13.1 +/- 3.13 in the cancer tissues and 43.0 +/- 6.74 in normal liver tissues. This difference of the lipid composition elucidates the instability of cytochrome P-450 molecules and the inefficiency of the electron transport of cytochrome P-450-linked monooxygenase systems.
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PMID:Microsomal cytochrome P-450-linked monooxygenase systems and lipid composition of human hepatocellular carcinoma. 254 14

Immunohistochemical localization of P-450 HFLa, a form of cytochrome P-450 in human fetal livers was investigated in human hepatocellular carcinoma. The cytoplasm of carcinoma cells positively reacted with anti-P-450 HFLa antibodies. It was found that the carcinoma cells showing a pseudoglandular pattern or poorly differentiated appearance exhibited a weaker reactivity with anti-P-450 HFLa antibodies than did relatively differentiated carcinoma cells. In the case of hepatoblastoma, the polygonal or round-shaped tumor cells which differentiated into epithelial structure exhibited a positive reaction with anti-P-450 HFLa antibodies, whereas the spindle-shaped tumor cells which showed a sarcomatous appearance did not react with the antibodies.
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PMID:Immunochemical studies for the presence of P-450 HFLa, a form of cytochrome P-450 in human fetal livers in human hepatocellular carcinoma cells. 255 Jun 7

The increase in serum gamma-glutamyl transpeptidase (GGT) is a well known marker of chronic alcoholism in man. We have previously shown that ethanol (180 mM) induces GGT activity 2-3-fold in the C2 rat hepatoma cell line. In this study, we have analyzed the interaction of ethanol with steroid hormones and drugs in this well defined cell culture system. Dexamethasone (100 nM), a synthetic glucocorticoid agonist, completely prevented the induction of GGT by ethanol, but had no effect when added alone. This inhibitory effect was also observed with other corticosteroids, but not with sex steroids; it was prevented by RU 486, a glucocorticoid antagonist. These observations suggest that dexamethasone acts through a high affinity glucocorticoid receptor. Conversely, ethanol did not interfere with the glucocorticoid induction of alanine aminotransferase in the same cell. We have analyzed the metabolism of ethanol in the C2 cells. These cells lack significant alcohol dehydrogenase activity as well as any cytochrome P-450 Alc immunoreactivity. Dexamethasone did not modify the disappearance of ethanol in the culture medium of those cells. We conclude that glucocorticoid hormones interact with ethanol at the cellular level, and that this interaction does not involve a modification of alcohol metabolism.
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PMID:Glucocorticoid hormones prevent the induction of gamma-glutamyl transpeptidase by ethanol in a rat hepatoma cell line. 256 56

The metabolism of albendazole (ABZ), a benzimidazole anthelminthic, was studied in either microsomal preparations of human liver biopsies or cultured human hepatoma cell lines. Metabolites were analyzed by HPLC. Our data show that microsomes from human biopsies and two human cell lines, HepG2 and Hep3B, oxidize the drug to the sulfoxide very efficiently, whereas the third cell line tested, SK-HEP-1, does not. Both cytochrome P-450 dependent monooxygenases and flavin-containing monooxygenases appear to be involved in human ABZ metabolism. Using the cell line displaying the highest ABZ-metabolizing activity, HepG2, the cytotoxic and the inducing effects of the parent drug ABZ and of two primary metabolites, the sulfoxide and the sulfone were studied. These three chemicals provoked a rise in mitotic index resulting from cell division blockage at the prophase or at the metaphase (ABZ metabolites) stage, and ABZ was more cytotoxic than its metabolites. With regard to enzyme-inducing effects, our data clearly demonstrate that the sulfoxide and, to a lesser degree, the sulfone are potent inducers of some drug metabolizing enzymes (i.e., cytochrome P-488 dependent monooxygenases and UDP glucuronyltransferase), whereas ABZ fails to increase and even slightly decreases these enzymatic activities. In conclusion, the HepG2 human hepatoma cell line appears to be suitable for the study of many parameters of metabolism and action of ABZ and other structurally related compounds in humans.
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PMID:Study of the in vitro bioactivation of albendazole in human liver microsomes and hepatoma cell lines. 256 53

Hepatoma 22a and Ehrlich's tumor growth were shown to be accompanied by decrease in cytochrome P-450 level in liver of noninbred and C3HA mice, these changes being more pronounced as compared to solid neoplasms. Benzo(a)pyrene-hydroxylase and amidopyrine-N-demethylase activity varied with tumor pattern. It was not changed in cases of hepatoma 22a but decreased in mice bearing Ehrlich's tumor, particularly, in those with the ascitic form. The inhibition analysis using metyrapone and 7,8-benzoflavone identified phenobarbital and methylcholanthrene forms of benzo(a)pyrene-hydroxylase in murine liver; isoform profile was not significantly affected by tumor. Liver microsomal monooxygenases of tumor-bearing mice retained inducibility by 3-methylcholanthrene.
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PMID:[Microsomal monooxygenases of the liver in mice with transplanted tumors]. 260 42

The metabolism of chemical carcinogens was investigated in liver preparations from 28 captive woodchucks (Marmota monax). Of these, 23 were naturally infected with the woodchuck hepatitis virus (WHV), and eight also had primary hepatocellular carcinoma (PHC). Twenty-nine parameters were investigated in liver subcellular fractions, including cross-reactivity with HBsAg, and biochemical parameters, such as gamma-glutamyl transpeptidase, cytochrome P-450 and microsomal monooxygenases (aryl hydrocarbon hydroxylase, ethoxycoumarin and ethoxyresorufin deethylases, aminopyrine and dimethylnitrosamine demethylases, and testosterone 7 alpha-, 16 alpha- and 6 beta-hydroxylases), uridine 5'-diphosphoglucuronosyl transferase, GSH and related enzymes (peroxidase, reductase and S-transferase), as well as other cytosolic enzyme activities (glucose 6-phosphate and 6-phosphogluconate dehydrogenases, NADPH- and NADH-dependent diaphorases, and DT diaphorase). In addition, liver preparations were used in order to quantify the metabolic activation into bacterial mutagens of five procarcinogens (aflatoxin B1, the pyrolysis products Trp-P-2 and MeIQ, 2-aminofluorene and dimethylnitrosamine) and the decrease of potency of three direct-acting mutagens (sodium dichromate, ICR 191 and 4-nitroquinoline 1-oxide). WHV infection produced a significant stimulation of carcinogen metabolism, as shown by the simultaneous change in detoxification parameters (GSH depletion) and activation indices (enhancement of microsomal monooxygenases and of procarcinogen activation into mutagenic metabolites). There were no significant differences between WHV-positive samples from animals without PHC and the noncancerous tissue of PHC-bearing animals, whereas a decrease of both activation and detoxification indices was recorded in the tumorous tissue. There was a considerable interindividual variability among WHV carriers, which was tentatively ascribed to genetic factors. Pregnancy was the only known factor influencing the results in WHV carriers. However, even by excluding pregnant animals, the effects on carcinogen metabolism produced by WHV infection were still statistically significant. These results, together with previous data obtained in humans, revealed that metabolic factors may play a role in the synergism between viral hepatitis and chemical hepatocarcinogens in the etiopathogenesis of PHC.
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PMID:Enhanced metabolic activation of chemical hepatocarcinogens in woodchucks infected with hepatitis B virus. 272 Sep 3

Immunohistochemical examinations were carried out for the study of cytochrome P-450 implication in the human hepatic disorders. An isozyme of human hepatic P-450 (P-450-HM1) with the m.w. of 51,000 was purified from human autopsied liver. Antibody against P-450-HM1 was prepared in rabbits, of which specificity was confirmed by Western blot. Eighty-three livers (27 autopsies and 56 biopsies, M:F = 63:20), which were either normal or of various hepatic disorders such as acute or chronic hepatitis, cirrhosis and hepatocellular carcinomas, were examined by the method of avidin-biotin-complex technique. It was revealed that immunoreactive hepatocytes were diffused throughout the lobule of the fetal liver. In the normal livers as well as those of acute and chronic hepatitis, positive hepatocytes were found in the centrilobular zone. Three of the 4 cases treated with beta-interferon showed faint staining; and the presence of positive individual hepatocytes was considered to be induced by steroid therapy. In the livers with chronic hepatitis and cirrhosis, hepatocytes near the perifibrous region and those trapped in the portal triad by thin fibrous connective tissue, as well as in the regenerating nodules, were strongly stained, which indicate that P-450-HM1 is expressed in the regenerating hepatocytes. Hepatocellular carcinomas, however, were devoid of immunohistochemistry. From these results, the antibody might be a useful tool for differentiating regenerating nodule from hepatocellular carcinoma.
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PMID:[Clinico-pathological studies of cytochrome P-450 on human hepatic disorders]. 276 18

In cultured human hepatoma cells phenolphthalein glucuronidation was increased 3-fold by 2 mM phenobarbitone (PB) in the culture medium but not by 25 microM benz(a)anthracene (BA), while 1-naphthol glucuronidation was not increased by either PB or BA. Ethoxyresorufin O-deethylation (EROD) was increased 15-fold by BA but not by PB, while the O-dealkylations of pentoxyresorufin (PROD) and benzyloxyresorufin (BROD) were increased by either PB or BA. The BROD activity increased by BA was sensitive to inhibition by alpha-naphthoflavone whereas that induced by PB was not. This suggests induction of different cytochrome P-450 isoenzymes. Control Hep G2 cells had similar glucuronide conjugation and cytochrome reductase activities to freshly isolated human adult hepatocytes, but had lower O-dealkylation and elevated microsomal epoxide hydrolase activities.
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PMID:Mixed function oxidase and UDP-glucuronyltransferase activities in the human Hep G2 hepatoma cell line. 284 53

When grown in the standard Dulbecco's medium the human liver derived Hep G2 hepatoma cell line shows only 10-20% of the cytochrome P-450-dependent mixed function oxidase (MFO) activity of freshly isolated human adult hepatocytes. However, the MFO activities and, to a lesser extent, the activities of UDP-glucuronyltransferase and glutathione-S-transferase can be increased by altering the composition of the growth medium. Modified Earle's medium was more effective in this respect than Williams' E medium and increased the O-dealkylations of ethoxyresorufin, benzyloxyresorufin and pentoxyresorufin 50-, 30- and 10-fold, respectively.
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PMID:The influence of culture medium composition on drug metabolising enzyme activities of the human liver derived Hep G2 cell line. 284 17


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