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)

Chlomethiazole (CMZ) is a sedative and anticonvulsant drug that has been shown to be an efficient transcriptional inhibitor of expression of rat hepatic ethanol-inducible cytochrome P-450 2E1 (CYP2E1). Recent results have shown that human CYP2E1 expression in vivo is almost completely inhibited in control subjects and in alcoholic patients treated with CMZ. In the present investigation, we evaluated the mode of action of CMZ on CYP2E1 expression in Fao rat hepatoma cells. Transcriptional activity of the CYP2E1 gene was monitored using reverse transcription-polymerase chain reaction-based quantification of CYP2E1 heterologous nuclear RNA (hnRNA) against a mimic DNA standard, mRNA was detected by Northern blotting, enzyme protein was detected by Western blotting, and CYP2E1-dependent catalytic activity was detected by assay of chlorzoxazone-6-hydroxylation. Six hours after CMZ treatment, the levels of both CYP2E1 protein and catalytic activity were concomitantly reduced at an IC50 value of about 5 microM. Ethanol treatment of the cells caused a 2-fold induction of CYP2E1 protein levels, which was inhibited by CMZ. Change of medium unexpectedly caused an increase in CYP2E1 gene transcription 4 h later, as monitored by quantitative determination of CYP2E1 hnRNA. However, CMZ failed to influence the expression of CYP2E1 hnRNA or mRNA both constitutively and after medium change, indicating no effect on gene transcription or mRNA synthesis/stability. Cycloheximide treatment of the cells did not abolish the inhibitory action of CMZ, further indicating an action at the post-translational level; in addition, CMZ inhibited CYP2E1 expression in V79 cells with stably expressed CYP2E1 under the control of the SV40 promoter. The data indicate that the CYP2E1 gene is transcriptionally activated in response to medium change and that CMZ, apart from a transcriptional inhibitor of CYP2E1 expression, acts in addition as an efficient high-affinity post-translational inhibitor of CYP2E1, probably due to an allosteric destabilization of the enzyme. This indicates a very rapid and effective CMZ-mediated inhibition of CYP2E1 in vivo.
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PMID:Post-translational inhibition of cytochrome P-450 2E1 expression by chlomethiazole in Fao hepatoma cells. 1021 62

The purpose of this study is to determine serum des-gamma-carboxy prothrombin (DCP) levels in benign liver diseases by a new sensitive method, and to demonstrate the elevation of serum DCP in alcoholic liver disease (ALD) without hepatocellular carcinoma (HCC). Median values of serum DCP were 16.2 mAU/ml (range: 3.2 to 1570 mAU/ml) in ALD and 16.7 mAU/ml (1.2 to 75.4 mAU/ml) in viral liver disease (VLD). Using the cut-off value of 40 mAU/ml as a tumor marker for HCC, 21% (11/52) was positive in ALD and 2% (1/57) was positive in VLD (p = 0.0014, Fisher's exact probability test), and 27% (9/33) was positive in alcoholic liver cirrhosis and 3% (1/39) was positive in viral liver cirrhosis (p = 0.0042, Fisher's exact probability test). The positive rate of DCP was significantly (p < 0.001, Spearman's rank correlation test) correlated with the severity of liver disease in ALD. Serum vitamin K level was not decreased in cases with ALD. In a demonstrable case, serum DCP was decreased after abstinence and was increased again after the beginning of ethanol intake, suggesting the involvement of ethanol to the elevation of serum DCP in ALD. In conclusion, serum DCP was significantly elevated in ALD, compared with VLD, although the mechanism of the elevation of DCP was not clarified. Ethanol intake may act, in part, on the increase of serum DCP in ALD.
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PMID:Increase of serum des-gamma-carboxy prothrombin in alcoholic liver disease without hepatocellular carcinoma. 1023 82

Ethanol-inducible cytochrome P450 2E1 (CYP2E1) involved in the metabolism of gluconeogenetic precursors and some cytotoxins is distinguished from other cytochrome P450 enzymes by its rapid turnover (in vivo half-life of 4-7 h), with ligands to the haem iron, both substrates and inhibitors, stabilizing the protein. CYP2E1 is also known to have a high oxidase activity in the absence of substrate, resulting in the production of reactive oxygen radicals. We suggested that the rapid intracellular turnover of the enzyme may be partly due to covalent modifications by such radicals or to other changes during catalytic cycling, in which case the inhibition of electron supply from NADPH-cytochrome P450 reductase would be expected to stabilize the protein. Fao hepatoma cells, where CYP2E1 showed a half-life of 4 h upon serum withdrawal, were treated for 1 h with 0.3 microM diphenylene iodonium (DPI), a suicide inhibitor of flavoenzymes, which resulted in approximately 90% inhibition of the microsomal NADPH-cytochrome P450 reductase and CYP2E1-dependent chlorzoxazone hydroxylase activities. Subsequent cycloheximide chase revealed that the CYP2E1 half-life increased to 26 h. Neither the degradation rates of total protein, CYP2B1 and NADPH-cytochrome P450 reductase nor the cellular ATP level were affected by DPI under the conditions employed. These results demonstrate for the first time that the short half-life of CYP2E1 in vivo may be largely due to the rapid destabilization of the enzyme during catalytic cycling rather than to the intrinsic instability of the protein molecule.
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PMID:Relationship between cytochrome P450 catalytic cycling and stability: fast degradation of ethanol-inducible cytochrome P450 2E1 (CYP2E1) in hepatoma cells is abolished by inactivation of its electron donor NADPH-cytochrome P450 reductase. 1033 89

The Long-Evans Cinnamon (LEC) rat is a mutant strain characterized by abnormal copper metabolism and a high incidence of hepatitis and hepatoma. Using a yeast-based assay which scores mutants in p53 gene transcripts as red colonies, we detected frequent mutations in the liver of LEC rats. The majority (50-60%) of these were frameshift mutations caused by the insertion of an extra adenine (A) in the regions containing six consecutive adenines. The rate of A insertion was calculated to be 6.9-9.0% of the total p53 cDNA. Insertions of an extra adenine were found almost exclusively in the mRNA (cDNA), especially in the (A)(6) tract located at the most 5'-side (exon 4) among the three (A)(6) tracts (exons 4, 7, and 8), but rarely in the corresponding sites of genomic DNA. Wild-type p53 cDNA was transcribed in vitro into mRNA with the use of SP6 RNA polymerase and tested by the yeast functional assay. Subsequent sequencing detected A insertions at an overall rate of 1.6% in exons 7 and 8 but none in exon 4. This indicates that the A insertion in the exon 4 (A)(6) tract was an in vivo phenomenon rather than an artifact in reverse transcription or polymerase chain reaction. The percentage of red colonies increased sharply to about 20% of the liver samples in the acute hepatitis stage, and returned to control level of those in the chronic hepatitis stage, and increased again slightly to those in the neoplastic stage. The percentage of red colonies correlated with the serum GOT level (r=0.96, p<0.001) but not with the contents of copper and 8-hydroxydeoxyguanosine in the liver of LEC rats. Ethanol treatment of hepatic cell lines also increased the rate of transcriptional slippage at the (A)(6) tract. These findings indicate that cellular damage is responsible for the increase in the rate of mutation at the transcriptional level, and suggest that cellular damage degrades transcriptional fidelity, thereby further impairing cellular functions.
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PMID:Transcriptional slippage of p53 gene enhanced by cellular damage in rat liver: monitoring the slippage by a yeast functional assay. 1075 4

The mechanisms by which ethanol inhibits hepatocyte proliferation have been a source of some considerable investigation. Our studies have suggested a possible role for tissue transglutaminase (tTG) in this process. Others have shown that tTG has two distinctly different functions: it catalyzes protein cross-linking, which can lead to apoptosis and enhancement of extracellular matrix stability, and it can function as a G protein (Galpha(h)). Under that circumstance, we speculated that the cross-linking activity would be decreased and that it would function to enhance hepatocyte proliferation in response to adrenergic stimulation. Ethanol treatment inhibited hepatocyte proliferation and led to enhanced tTG cross-linking activity, whereas treatment of hepatocytes with an alpha1 adrenergic agonist, phenylephrine, enhanced hepatocyte proliferation while decreasing tTG cross-linking. However, phenylephrine treatment of several hepatoma cell lines had no effect on cellular proliferation or tTG cross-linking activity, and of note, Northern blot analysis demonstrated that whereas primary hepatocytes had high levels of the alpha1beta adrenergic receptor (alpha1BAR) mRNA, the hepatoma cell lines did not have this mRNA. When the Hep G(2) cell line was stably transduced with an expression vector containing the alpha1BR cDNA, the cell line responded to phenylephrine treatment with enhanced proliferation and with decreased tTG cross-linking activity. Ethanol treatment of the alpha1BAR-transfected cells suppressed the phospholipase C-mediated signaling pathways, as detected in the phenylephrine-induced Ca(2+) response. These results suggest that phenylephrine stimulation of hepatocyte proliferation appears to be occurring through the alpha1BAR, which is known to be coupled with the tTG G protein moiety, Galpha(h), and that tTG appears to play a significant role in either enhancing or inhibiting hepatocyte proliferation, depending on its cellular location and on whether it functions as a cross-linking enzyme or a G protein.
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PMID:Roles of tissue transglutaminase in ethanol-induced inhibition of hepatocyte proliferation and alpha 1-adrenergic signal transduction. 1080 82

Fatty acids are ligands for the peroxisome proliferator-activated receptor alpha (PPAR alpha). Fatty acid levels are increased in liver during the metabolism of ethanol and might be expected to activate PPAR alpha. However, ethanol inhibited PPAR alpha activation of a reporter gene in H4IIEC3 hepatoma cells expressing alcohol-metabolizing enzymes but not in CV-1 cells, which lack these enzymes. Ethanol also reduced the ability of the PPAR alpha ligand WY14,643 to activate reporter constructs in the hepatoma cells or cultured rat hepatocytes. This effect of ethanol was abolished by the alcohol dehydrogenase inhibitor 4-methylpyrazole and augmented by the aldehyde dehydrogenase inhibitor cyanamide, indicating that acetaldehyde was responsible for the action of ethanol. PPAR alpha/retinoid X receptor extracted from hepatoma cells exposed to ethanol or acetaldehyde bound poorly to an oligonucleotide containing peroxisome proliferator response elements. This effect was also blocked by 4-methylpyrazole and augmented by cyanamide. Furthermore, in vitro translated PPAR alpha exposed to acetaldehyde failed to bind DNA. Thus, ethanol metabolism blocks transcriptional activation by PPAR alpha, in part due to impairment of its ability to bind DNA. This effect of ethanol may promote the development of alcoholic fatty liver and other hepatic consequences of alcohol abuse.
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PMID:The transcriptional and DNA binding activity of peroxisome proliferator-activated receptor alpha is inhibited by ethanol metabolism. A novel mechanism for the development of ethanol-induced fatty liver. 1102 51

To study the effect of the different interventional treatment on P-Glycoprotein (Pgp) in different histopathological types of primary hepatocellular carcinoma (PHC), 98 surgically and histologically verified PHC specimens were obtained. The patients included 57 patients treated by surgical resection alone and 41 patients receiving second-stage surgical resection after four kinds of interventional treatment. SABC immunohistochemical staining with a monoclonal antibody against human Pgp was used to observe the Pgp in all specimens. The positive rate of Pgp was 100% in group of chemotherapy alone (P < 0.05), 62.5% in group of chemotherapy combined with iodized oil (P > 0.05), 46.6% in group of chemotherapy combined with iodized oil and spongia gelatini absorbens (Sga) (P > 0.05), 18.18% in group of chemotherapy combined with Ethanol-iodized-oil and Sga (P < 0.05) and 52.63% in group of surgical resection alone. The positive rate of Pgp varied with different histopathological types, with rate of clear cell PHC being the lowest, and that of poorly differentiated or undifferentiated PHC the highest. The positive rate of Pgp was increased as pathological grades increased. Overexpression of Pgp may be responsible for the intrinsic and acquired drug resistance of PHC. Multidrug resistance (MDR) varied with different histological types. Therapy of PHC should be tailored according to individual. Local chemotherapy combined with ethanol-iodized-oil and Sga embolization may become a new way to overcome MDR of PHC.
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PMID:The effect of different interventional treatment on P-Glycoprotein in different histopathological types and grades of primary hepatocellular carcinoma. 1121 58

Ethanol injection into HCC tumors is an effective therapy and percutaneous ethanol injection therapy (PEIT) is performed on many HCC patients. However, there are cases in which PEIT becomes difficult because the HCC could not be detected by ultrasonography or the tumor is located in an area where it is impossible to perform PEIT. Nine patients with HCC underwent laparoscopic ethanol injection therapy (LEIT) in our institution. Their tumors were located on the liver surface and could be visualized by laparoscopic examination. Ethanol injection was performed under laparoscopic direct visualization. The total injected ethanol volume required ranged from 4 to 15 ml and in most cases both tumor size and alpha-fetoprotein (AFP) levels decreased after LEIT. Three cases showed a transient complication of abdominal pain or/and portal vein damage. Other severe complications were not observed. All cases required additional therapies, including transcatheter arterial chemoembolization (TAE) or PEIT to complete the tumor necrosis. In conclusion, LEIT is a safe and effective therapy for HCC located on the liver surface, but should be combined with other therapies to facilitate its effect against HCC.
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PMID:Laparoscopic ethanol injection therapy for hepatocellular carcinoma. 1178 87

The influence of both short- and long-term ethanol exposure on the lipid metabolism was determined in the human hepatoma cell line HepG2. Ethanol did not cause any cytotoxicity or lipid peroxidation even after 7 days of 100 mM ethanol treatment of HepG2 cells. Incubation of cells in the presence of [1-(14)C]ethanol demonstrated that these cells actively metabolize ethanol to acetyl CoA, incorporating the radioactive label into neutral lipids and phospholipids. [1,2,3-(3)H]glycerol was efficiently used in phospholipid and neutral lipid biosynthesis, showing higher radioactivity in phosphatidylcholine, phosphatidylethanolamine and triacylglycerols. Exposure of HepG2 cells to 100 mM ethanol for 24 hr did not significantly modify the incorporation of glycerol into newly synthesized phospholipids and neutral lipids, nor was lipid degradation affected by the presence of ethanol. When the alcohol treatment was prolonged for 7 days, incorporation of [1,2,3-(3)H]glycerol into triacylglycerols and diacylglycerols showed a slight increase concomitantly with decreased radioactivity in the major phospholipids, phosphatidylcholine and phosphatidylethanolamine. In addition, these changes were associated with a greater release of radiolabeled triacylglycerols into the culture medium. These results indicate that ethanol does not cause in HepG2 cells the marked lipogenic stimulation widely shown in hepatocytes, and demonstrate that HepG2 cells strongly resist the adverse effects of ethanol. Since these cells lack the isoenzymatic form of cytochrome P(450) mainly involved in the ethanol metabolism (namely cytochrome P(450)2E1) and also are devoid of alcohol dehydrogenase activity, we propose that the toxic actions of ethanol on liver must be linked to the activity of one or both of these systems.
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PMID:Resistance of HepG2 cells against the adverse effects of ethanol related to neutral lipid and phospholipid metabolism. 1199 90

Bile leakage after hepatic resection often results in the formation of a biliary-cutaneous fistula. Such a fistula, when caused by an isolated bile duct in the remnant liver, can be intractable. We report a successful case of ethanol injection therapy of an isolated bile duct. A 73-year-old man underwent right hepatic resection for hepatocellular carcinoma. Bile leakage occurred after surgery, and the patient developed a biliary-cutaneous fistula. Fistulography revealed an isolated bile duct in the remnant portion of the caudate lobe without communication to the main biliary system. As conservative management with simple drainage was ineffective, injection therapy with ethanol was performed with a balloon occlusion catheter. After 11 therapy sessions, the bile duct was eradicated, and the biliary- cutaneous fistula was completely healed. The post-treatment course was uneventful. Ethanol injection therapy can be a choice for management of patients with a biliary fistula caused by an isolated bile duct.
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PMID:Ethanol injection therapy of an isolated bile duct associated with a biliary-cutaneous fistula. 1212 14


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