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)

Dehydroepiandrosterone (DHEA) given to rodents in pharmacological doses induces several hepatic enzymes including cytochromes P4504A, NADPH:P450 oxidoreductase, palmitoyl coenzyme A oxidase, and other enzymes associated with the peroxisomal beta-oxidation pathway, leading to peroxisome proliferation and development of hepatocellular carcinoma in rodents. Comparison of the inductive potency of DHEA and other intermediates of the steroid biosynthetic path demonstrated that only DHEA, 5-ene-androstene-3 beta,17 beta-diol (ADIOL), and to a lesser extent, 17 alpha-hydroxypregnenolone, a precursor of DHEA, induce cytochromes P4504A protein and other enzymes associated with the peroxisome proliferative response in vivo. ADIOL exerted its inductive response at a somewhat lower dosage than DHEA, whereas ADIOL and DHEA both induced the microsomal enzymes (P4504A and its oxidoreductase) at somewhat lower dosages than those required to induce peroxisomal enzymes. Northern analysis demonstrated increases in the mRNAs encoding the cytochromes P4504A (> 20-fold) and NADPH:P450 oxidoreductase (> 10-fold) in the livers of DHEA- and ADIOL-treated rats. Run-on transcription analysis demonstrated that DHEA induces CYP4A gene expression 11-fold at the level of transcription initiation. Comparison of the responsiveness of individual rat CYP4A genes (4A1, 4A2, and 4A3) to DHEA and ADIOL in immature versus mature male rats revealed 2-3-fold higher levels of induced CYP4A1 and 4A3 mRNAs in immature rat livers. In contrast, hepatic CYP4A2 mRNA was induced to 6-10-fold higher levels in mature rats. No basal or significant inducible expression of mRNA for CYP4A1 and 4A3 was noted in rat kidney. Significant basal levels of kidney CYP4A2 mRNA were observed only in mature animals, where they were inducible by ADIOL and DHEA to a 3-5-fold greater extent than in the kidneys of immature rats. These studies demonstrate developmental differences in the responsiveness of CYP4A mRNA levels to DHEA and ADIOL in rat kidney and liver. Moreover, the striking inducibility of CYP4A protein and mRNAs, together with the increased rates of synthesis of nascent CYP4A mRNA transcripts in hepatic nuclei from DHEA-treated rats, establish that DHEA increases the expression of these microsomal enzymes at the transcriptional level.
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PMID:Induction of microsomal and peroxisomal enzymes by dehydroepiandrosterone and its reduced metabolite in rats. 818 72

Interleukin 8 (IL-8) is a recently described cytokine that functions as a potent neutrophil chemoattractant and activator. We sought to examine the link between the generation of reactive oxygen intermediates (ROI) and the regulation of IL-8 gene expression to specifically test the hypothesis that ROI would induce production of IL-8 mRNA and protein. In lipopolysaccharide-stimulated human whole blood, the OH radical scavenger dimethyl sulfoxide (Me2SO) dramatically inhibited (approximately 90%) IL-8 production, but had minimal effects on the production of tumor necrosis factor, interleukin 1 beta (IL-1), and IL-6. To determine whether NADPH-oxidase-generated free radicals were critical in the regulation of IL-8, studies were performed using blood from patients with chronic granulomatous disease. In both normal individuals and patients with chronic granulomatous disease, production of IL-8 could be initiated with lipopolysaccharide, phytohemagglutinin, or aggregated immune complexes, and this production could be inhibited by Me2SO (1% v/v). To examine if oxidant stress represents a ubiquitous mechanism for the induction of IL-8, experiments were performed in cultured cell lines. In the human hepatoma cell line Hep-G2, Me2SO dose-dependently inhibited tumor necrosis factor-stimulated IL-8 production, with a 74 +/- 1% reduction observed at a Me2SO concentration of 1%. Direct exposure to ROI demonstrated that H2O2 stimulated IL-8 production in a dose-dependent manner in Hep-G2 cells, A549 pulmonary type II epithelial cells, and human skin fibroblasts; this induction could be prevented by addition of catalase. The production of IL-8 appeared to be specific to an oxidant stress since exposure of the cells to heat shock or chemical stress did not induce expression of IL-8. These studies demonstrate that oxidant stress is an important regulator of IL-8 gene expression and support the hypothesis that low levels of ROI may serve to initiate IL-8 production which then serves to recruit neutrophils to sites of inflammation.
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PMID:Regulation of interleukin 8 gene expression by oxidant stress. 824 94

Glutathione peroxidase is an important enzyme in cellular antioxidant defense systems, detoxifying peroxides and hydroperoxides. As a component of the glutathione cycle, it protects the liver from reactive oxygen metabolites. Selenocysteine is present at the catalytic site of glutathione peroxidase, and selenium availability regulates glutathione peroxidase enzyme activity. Hep3B cells, a well-differentiated human hepatoma-derived cell line, exhibited time-dependent decrease in glutathione peroxidase activity (nmol NADPH oxidized/min/mg protein, mean +/- SE) when incubated in selenium-free medium for 10 days (Day 0, 21.8 +/- 7.3; Day 2, 10.9 +/- 1.2; Day 4, 7.9 +/- 0.8; Day 6, 4.0 +/- 0.7; Day 8, 4.5 +/- 0.6; Day 10, 1.6 +/- 0.4). With the reintroduction of selenium, glutathione peroxidase activity returned. A second human hepatoma cell line, HepG2, demonstrated a similar pattern when depleted of and then repleted with selenium. To assess protein synthesis, glutathione peroxidase activity was measured in deficient and replete Hep3B cells incubated with and without selenium and with and without cycloheximide. Deficient cells (mean +/- SE) (4.9 +/- 0.2) showed an increase in glutathione peroxidase activity after 24 h in selenium-containing medium (11.6 +/- 0.2), but not when cycloheximide was included in the medium (6.9 +/- 0.5) or when cycloheximide and no selenium was included (5.3 +/- 0.8). Replete Hep3B cells (40.1 +/- 1.1) demonstrated decreased glutathione peroxidase after 24 h in medium without selenium (34.0 +/- 1.4), medium with both cycloheximide and selenium (34.0 +/- 2.6), and medium without selenium and containing cycloheximide (37.6 +/- 1.3). These data suggest that protein synthesis is needed for selenium repletion to exert control on glutathione peroxidase activity. Using a cDNA for human glutathione peroxidase (GPx1), selenium-deficient and replete Hep3B cell RNA was analyzed by Northern blot. mRNA for GPx was quantified by densitometry. The steady-state mRNA level for glutathione peroxidase in deficient cells was 40% of that in replete cells. Nuclear run-on studies to determine the rate of GPx-specific mRNA synthesis showed no difference between nuclei from selenium-replete and selenium-deficient cells. This finding eliminated the possibility of differential transcription rates as an explanation for the observed reduction in mRNA brought about by selenium deficiency and suggested instead a stabilization of mRNA in selenium-replete cells. While selenium deficiency decreased mRNA levels by 60%, glutathione peroxidase enzyme activity decreased by 93%, suggesting a co- and/or post-translational control mechanism in addition to the effect on mRNA stability.
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PMID:Selenium regulation of glutathione peroxidase in human hepatoma cell line Hep3B. 839 84

Eight polycyclic aromatic hydrocarbon (PAH) ortho-quinones that can be generated by dihydrodiol dehydrogenase (DD) were examined for their cytotoxicity in H-4-II-e (rat hepatoma) cells and for their mutagenicity in the Ames test. Seven of the PAH otrtho-quinones were potent cytotoxins yielding IC50 values for cell survival in the range 1-30 microns. PAH ortho-quinones were grouped into three classes based on their cytotoxicity profiles: group I contained ortho-quinones (e.g., naphthalene-1,2-dione and 7,12-dimethylbenz[alpha]anthracene-3,4-dione) which reduced cell viability and cell survival; group II contained ortho-quinones (e.g., benz[alpha]anthracene-3,4-dione and 5-methylchrysene-1,2-dione which reduced cell survival but had no effect on cell viability; and group III contained ortho-quinones (e.g., benzo[alpha]pyrene-7,8-dione) which had a pronounced effect on cell viability but minimal effects on cell survival. Using hepatoma cell suspensions and rat liver subcellular fractions, it was found that ortho-quinones underwent preferential enzymatic one-electron redox-cycling and produced superoxide anion radical (O2-.) and/or ortho-semiquinone anion or alternant radicals. ortho-Quinones that reduced cell viability produced O2-. and caused the most total free radical formation, while those that reduced cell survival produced ortho-semiquinone anion or alternant radicals only. PAH ortho-quinones were also tested as direct-acting mutagens in Salmonella typhimurium tester strains TA97a, TA98, TA100, TA102 and TA104. They were found to be more mutagenic than the test mutagens used for each tester strain, and were predominantly frameshift mutagens. The presence of an activating system (Aroclor-induced rat liver S9 plus NADPH) did not increase the mutagenicity of ortho-quinones in tester strains that are sensitive to oxidative mutagens (TA102 and TA104). These data suggest that PAH ortho-quinones produced by DD are cytotoxic and mutagenic by different mechanisms. The mechanism of cytotoxicity involves the formation of reactive oxygen species and/or ortho-semiquinone anion or alternant radicals. The mechanism of mutagenicity is independent of free radical formation and is related to the ability of PAH orthooffinones to intercalate and covalently modify DNA.
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PMID:Cytotoxicity and mutagenicity of polycyclic aromatic hydrocarbon ortho-quinones produced by dihydrodiol dehydrogenase. 862 May 79

We have recently proposed a H2O2-generating b-type cytochrome as part of the cellular oxygen sensor that controls O2-dependent erythropoietin (Epo) production in the human hepatocellular carcinoma cell line HepG2. H2O2 could act as an intracellular signaling molecule because its production in HepG2 cells is strictly dependent on the pericellular PO2. High cellular levels of H2O2 inhibit hypoxia-induced Epo production while low levels-as under hypoxic conditions-allow full expression of the Epo gene. Since cobalt chloride (CoCl2) and the iron chelator desferrioxamine (DSF) both mimic the hypoxic induction of Epo production we studied the influence of CoCl2 and DSF on the formation and on the action of reactive O2-species with respect to Epo production. Both chemicals reduced the H2O2-dependent 123-dihydrorhodamine fluorescence in HepG2 cells. The inhibition of Epo production by exogenous H2O2 was completely antagonized by DSF. This might indicate that H2O2 exerts its inhibition through a Fenton type reaction. On the other hand, NADPH and pyrogallol which stimulate the production of O2- inhibited Epo production. CoCl2 antagonized their effects. From our results we propose different sites of interaction with the putative signaling chain for DSF and CoCl2. While DSF appears to reduce the action of the H2O2 molecule, CoCl2 might act further upstream through the induction of H2O2-scavenger systems or by interfering with its production.
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PMID:Cobalt chloride and desferrioxamine antagonize the inhibition of erythropoietin production by reactive oxygen species. 902 28

The current study demonstrates that T3-activated transcription of the NADPH:cytochrome P450 oxidoreductase (P450R) gene is dependent on the thyroid hormonal status of the animal, with both transcriptional and post-transcriptional pathways being important in regulating the cellular P450R mRNA level. The region required for transcriptional activation of the P450R gene by T3 has been identified. Nuclear run-on experiments demonstrated that the effects of T3 on P450R transcription are dependent on thyroid status, with a transcriptional enhancement obtained in T3-treated hypothyroid rat liver (1.8-fold increase) but not in T3-treated euthyroid animals. Transient cotransfection of P450R promoter/chloramphenicol acetyl transferase (CAT) constructs and the thyroid hormone receptor beta1 (TR beta1) expression plasmid into rat hepatoma H4IIE cells resulted in a 2.4-fold induction of promoter activity that was both T3 and TR beta1 dependent. Analysis of promoter deletion constructs identified a P450R-thyroid response region (P450R-TRE; bases, -564 to -536) containing three imperfect direct repeats of the thyroid response motif, AGGTCA. Mutational analysis further established that T3 induction was dependent only on the upstream direct repeat, having the sequence AGGTGAgctgAGGCCA. Footprint analysis showed that all three motifs were protected by proteins present in rat liver nuclear extracts, and a direct interaction between P450R-TRE and T3 receptors TR alpha1 and TR beta1 was demonstrated by gel-shift analysis. In vitro binding studies with P450R-TRE revealed the formation of heterodimeric complexes when TR alpha1 was coincubated with either the retinoic X receptor alpha or nuclear extract from rat liver, COS, or H4IIE cells. In addition, placement of the P450R-TRE upstream of the T3-nonresponsive heterologous thymidine kinase promoter resulted in a 2.7-fold transcriptional enhancement that was both T3 and TR beta1 dependent. Previous studies have demonstrated that T3 augments P450R mRNA levels approximately 20-30-fold and approximately 12-fold, respectively, in hypothyroid and euthyroid rats. Hence, for the hypothyroid state, transcriptional and post-transcriptional events contribute to the T3-induced mRNA increases; however, the marked increase in message level in T3-treated euthyroid animals depends primarily on post-transcriptional pathways.
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PMID:Thyroid regulation of NADPH:cytochrome P450 oxidoreductase: identification of a thyroid-responsive element in the 5'-flank of the oxidoreductase gene. 922 11

Erythropoietin (Epo) synthesis is suppressed in normoxia and stimulated in hypoxia. To test the hypothesis that the cellular H2O2 level is important in the control of Epo synthesis, we have studied effects of modulators of H2O2 generation and degradation on Epo production in human hepatic cell cultures (hepatoma lines HepG2 and Hep3B). In addition, we measured the activities of antioxidant enzymes (catalase, superoxide dismutase, glutathione peroxidase) in cultures following hypoxia exposure or H2O2 treatment. The results show that the formation of immunoreactive Epo was stimulated in normoxic cultures by treatment with exogenous catalase thus mimicking the effect of hypoxia (24 h incubation periods). Epo production was also stimulated when scavengers of reactive O2 species (tetramethylthiourea, dihydrorhodamine) were added to the cells. On the other hand, stimulators of H2O2 generation (xanthine oxidase, glucose oxidase, NADH, NADPH) lowered Epo production in hypoxic cultures. Hypoxia exposure decreased superoxide dismutase activity and H2O2 treatment reduced catalase activity thus influencing the endogenous antioxidant defense system. These findings support the concept that reactive O2 species, primarily H2O2, act as messengers in the O2-dependent control of the hepatic production of Epo. Changes in the cellular activities of antioxidant enzymes appear to play only a minor role in this process.
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PMID:Effects of modulators of the production and degradation of hydrogen peroxide on erythropoietin synthesis. 986 91

A functional cytochrome P4501A1 (CYP1A1) enzyme has been suggested to metabolize endogenous substrates and to autoregulate its own transcription in mouse hepatoma cells. In the present study, the regulation of CYP1A1 gene transcription by 6-formylindolo[3,2-b]carbazole (FICZ), a suggested endogenous ligand for the aryl hydrocarbon receptor (AhR), has been studied in mouse Hepa-1 cell lines. The tryptophan photoproduct, FICZ, has previously been characterized to possess very high AhR binding affinity and to transiently induce CYP1A1 gene expression in cultured cells at picomolar concentrations. The results from this study show that a transient induction of CYP1A1 mRNA at a low concentration of FICZ was only seen in wild-type cells. In c37 cells, deficient in CYP1A1, FICZ caused a sustained induction. Interestingly, we found that a higher amount of tryptophan in culture medium increased the constitutive level of CYP1A1 mRNA expression in the c37 cells but not in the wild-type cells. This suggests that a tryptophan-derived AhR ligand in the medium regulates the basal CYP1A1 expression. In metabolism studies performed with S9 prepared from c37 cells no metabolites were formed from FICZ and no loss of FICZ was observed, while with wild-type cells FICZ was rapidly metabolized. HPLC analysis revealed that at least three metabolites were formed in an NADPH-dependent manner from FICZ when incubated with rat liver S9. The CYP1A1 inhibitor ellipticine totally blocked the metabolism of FICZ. Ellipticine also enhanced both basal and FICZ-induced CYP1A1 mRNA expression. Taken together, these results indicate that tryptophan is a precursor of the endogenous ligand and that the suggested tryptophan-derived ligand FICZ is a substrate for the CYP1A1 enzyme and is involved in autoregulation of CYP1A1 transcription.
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PMID:Regulation of CYP1A1 transcription via the metabolism of the tryptophan-derived 6-formylindolo[3,2-b]carbazole. 1109 81

The effects of water extracts from Cassia tora L. (WECT) treated with different degrees of roasting on benzo[a]pyrene (B[a]P)-induced DNA damage in human hepatoma cell line HepG2 were investigated via the comet assay without exogenous activation mixtures, such as S9 mix. WECT alone, at concentrations of 0.1-2 mg/mL, showed neither cytotoxic nor genotoxic effect toward HepG2 cells. B[a]P-induced DNA damage in HepG2 cells could be reduced by WECT in a dose-dependent manner (P < 0.05). At a concentration of 1 mg/mL, the inhibitory effects of WECT on DNA damage were in the order unroasted (72%) > roasted at 150 degrees C (60%) > roasted at 250 degrees C (23%). Ethoxyresorufin-O-dealkylase activity of HepG2 cells was effectively inhibited by WECT, and a similar trend of inhibition was observed in the order unroasted (64%) > roasted at 150 degrees C (42%) > roasted at 250 degrees C (18%). The activity of NADPH cytochrome P-450 reductase was also decreased by unroasted and 150 degrees C-roasted samples (50% and 38%, respectively). Furthermore, glutathione S-transferase activity was increased by treatment with unroasted (1.26-fold) and 150 degrees C-roasted (1.35-fold) samples at 1 mg/mL. In addition, the contents of anthraquinones (AQs) in WECT, including chrysophanol, emodin, and rhein, were decreased with increasing roasting temperature. Each of these AQs also demonstrated significant antigenotoxic activity in the comet assay. The inhibitory effects of chrysophanol, emodin, and rhein on B[a]P-mediated DNA damage in HepG2 cells were 78, 86, and 71%, respectively, at 100 microM. These findings suggested that the decreased antigenotoxicity of the roasted samples might be due to a reduction in their AQs content.
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PMID:Inhibitory effects of Cassia tora L. on benzo[a]pyrene-mediated DNA damage toward HepG2 cells. 1136 39

PR-39, which is an endogenous antimicrobial peptide, can bind to Src homology 3 domains of the NADPH complex protein p47(phox) and the signaling adapter protein p130(Cas). Recently, we have reported that PR-39 gene transduction altered invasive activity and actin structure of human hepatocellular carcinoma cells, suggesting that this peptide affects cellular signaling due to its proline-rich motif. In order to clarify the mechanism of the PR-39 functions, we transfected the PR-39 gene into mouse NIH3T3 cells which had already been transformed with human activated k-ras gene. The PR-39 gene transfectant showed a reorganization of actin structure and suppression of cell proliferation both in vitro and in vivo. Decreases of MAP (mitogen-activated protein) kinase activity, cyclin D1 expression and JNK activity were observed in the PR-39 gene transfectant. Co-immunoprecipitation analysis revealed that PR-39 binds to PI3-kinase p85alpha, which is a regulatory subunit of PI3-kinase and one of the effectors by which ras induces cytoskeletal changes and stimulates mitogenesis. The PI3-kinase activity of the PR-39 gene transfectant was decreased compared with that of the ras transformant. These results suggest that PR-39 alters actin structure and cell proliferation rate by binding to PI3-kinase p85alpha and suppressing the PI3-kinase activity.
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PMID:PI3-kinase p85alpha is a target molecule of proline-rich antimicrobial peptide to suppress proliferation of ras-transformed cells. 1157 64


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