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)

Thus far, a large number of hypothesis have been proposed to explain how ethanol causes liver diseases including fatty liver, hepatitis, hepatic fibrosis, cirrhosis, as well as hepatocellular carcinoma. Although it still remains obscure, recent progress of science enables us to understand the mechanisms more deeply. We reviewed the latest aspects of mechanisms of alcoholic liver diseases, including alteration of redox state, effects of acetaldehyde and acetate, changes of metabolisms of lipid and protein, production of free radicals, alteration of hepatic micro circulation, change of hepatic membrane composition followed by changes of intracellular signal transduction, and effects of endotoxin. Moreover, we discussed the recent progress of studies on enzyme systems which participate in ethanol metabolism.
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PMID:[Recent progression in research on alcoholic liver disease]. 904 44

It has been shown previously that oxidative stress by ferrous iron in vitro leads to an inhibition of proliferation of murine ascites tumour cells in vivo. This effect is associated with increased lipid peroxidation in terms of formation of the highly reactive aldehyde 4-hydroxynonenal (HNE), which has been shown to inhibit the proliferation of numerous tumours and to induce differentiation. It was the purpose of this article to study the occurrence and metabolism of HNE and its inducibility by oxidative stress in hepatomas of different degrees of differentiation to find further evidence for a possible role of HNE in proliferation and/or differentiation, because it is known that in hepatoma cells with a very low degree of differentiation basal lipid peroxidation is hardly detectable, while in normal hepatocytes the basal level of thiobarbituric acid reactive substances (TBArS) is rather high. MH1C1 hepatoma cells and Yoshida AH-130 hepatoma cells were chosen as highly differentiated and poorly differentiated tumour cells, respectively, and rat hepatocytes served as a control for normal liver phenotype. Ferrous histidinate (Fe/His) did not have a cytotoxic effect on Yoshida and MH1C1 cells, as measured by the LDH release test. In cell culture studies Fe/His revealed a dose dependent inhibition of the proliferation of Yoshida cells. The incorporation of 3H-thymidine into DNA of these cells was also inhibited by Fe/His in a dose-dependent manner, while the precursor uptake into the cytoplasm was unaffected. The basal levels of HNE were in the order: hepatocytes > MH1C1 cells > Yoshida cells. Both hepatocytes and Yoshida cells responded to the presence of Fe/His with increased formation of TBArS. Compared with hepatocytes the response of the Yoshida cells was greatly reduced. The response of cells to Fe/His with respect to HNE formation was decreased in the order: hepatocytes > MH1C1 cells > Yoshida cells, but in this case the differences were not very pronounced. The metabolic capacity of the cells to consume HNE was also decreased in the order: hepatocytes > MH1C1 cells > Yoshida cells. In this case the differences were very pronounced. These findings support the view that Yoshida cells with a low degree of differentiation and a low basal level of HNE are released from an inhibitory effect of HNE operative in hepatocytes and that HNE is causally involved in the iron induced inhibition of proliferation of poorly differentiated hepatoma cells.
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PMID:Effect of oxidative stress by iron on 4-hydroxynonenal formation and proliferative activity in hepatomas of different degrees of differentiation. 916 94

The metabolism of acetaldehyde (ACA), benzaldehyde (BA), propionaldehyde (PA) and valeraldehyde (VA) has been studied in two hepatoma cell lines, the rat HTC and mouse Hepa 1c1c7 cells. The cytotoxicity of the four aldehydes to these two cell lines has been compared. The end-points for evaluating cytotoxicity were 1) total macromolecular content (TMC) of confluent cultures, and 2) colony forming ability of dividing cells. These two assay systems had different sensitivities for the toxicity of aldehydes, probably due to different numbers of target cells. The activities of aldehyde dehydrogenases (NAD- and NADP-dependent, ALDH), alcohol dehydrogenase and aldehyde reductase were markedly greater in the HTC cell line compared to the Hepa 1c1c7 cell line, especially with BA as substrate. The cytotoxicities of aldehydes were generally stronger in the HTC cell line than in the Hepa 1c1c7 cell line; with the CF test. Particularly, BA was highly toxic to the HTC cells, which possessed the highest ALDH levels. Moreover, the treatment with (diethylamino)benzaldehyde, an ALDH inhibitor, completely abolished the toxicity of BA. Taken together, all these findings suggest that several cell lines expressing different aldehyde metabolizing activities could be used especially in the pre-screening phase to distinguish the metabolism-dependent cytotoxic effects from the metabolism independent effects.
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PMID:Comparative evaluation of cytotoxicity and metabolism of four aldehydes in two hepatoma cell lines. 929 76

Benzo(a)pyrene (BaP), a prototype of polycyclic aromatic hydrocarbons (PAHs), is a potent procarcinogen generated during the combustion of fossil fuels and cigarette smoke. In addition to the carcinogenic and mutagenic effects, BaP and other PAHs, including 7,12-dimethylbenz[a]anthracene and 2,3,7,8-tetrachlorodibenzo[p]dioxin, have been shown to induce programmed cell death or apoptosis. However, the molecular mechanisms by which PAHs such as BaP induce apoptosis are not clear. To investigate the molecular events leading to apoptosis induced by BaP, we studied the involvement of the interleukin 1beta-converting enzyme (ICE)/Ced-3 family of proteases (caspases) and c-Jun NH2-terminal kinase 1 (JNK1), which have been shown to mediate numerous extracellular stimuli-induced apoptosis. On treatment of mouse Hepa 1c1c7 hepatoma cells with BaP, the induction of apoptosis, as determined by genome digestion, was observed at concentrations of 1-30 microM after 24 h of treatments. Importantly, at the apoptosis-inducing concentrations, BaP also induced the activation of an ICE/Ced-3 cysteine protease caspase-3 but not caspase-1 (ICE). The activation of caspase-3 by BaP preceded apoptosis. Furthermore, a specific inhibitor of caspase-3-like proteases, acetyl-Asp-Glu-Val-Asp-aldehyde, significantly blocked caspase-3 activity and attenuated apoptosis induced by BaP. Treatment with BaP also caused a time- and dose-dependent activation of JNK1 activity. Interestingly, a much lower concentration (5 nM), as well as much earlier kinetics, were observed in JNK1 activation as compared with caspase-3 activation or induction of apoptosis by BaP. In summary, our results demonstrate that BaP induced apoptosis in the mouse hepatoma Hepa1c1c7 cell line via a caspase-dependent pathway, which may be independent of JNK activation.
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PMID:Induction of apoptosis and activation of interleukin 1beta-converting enzyme/Ced-3 protease (caspase-3) and c-Jun NH2-terminal kinase 1 by benzo(a)pyrene. 960 52

A great number of epidemiological data have identified chronic alcohol consumption as a significant risk factor for upper alimentary tract cancer, including cancer of the oropharynx, larynx, and the esophagus, and for the liver. In contrast to those organs, the risk by which alcohol consumption increases cancer in the large intestine and in the breast is much smaller. However, although the risk is lower, carcinogenesis can be enhanced with relatively low daily doses of ethanol. Considering the high prevalence of these tumors, even a small increase in cancer risk is of great importance, especially in those individuals who exhibit a higher risk for other reasons. The epidemiological data on alcohol and other organ cancers are controversial and there is at present not enough evidence for a significant association. Although the exact mechanisms by which chronic alcohol ingestion stimulates carcinogenesis are not known, experimental studies in animals support the concept that ethanol is not a carcinogen, but under certain experimental conditions is a cocarcinogen and/or (especially in the liver) a tumor promoter. The metabolism of ethanol leads to the generation of acetaldehyde and free radicals. These highly reactive compounds bind rapidly to cell constituents and possibly to DNA. Acetaldehyde decreases DNA repair mechanisms and the methylation of cytosine in DNA. It also traps glutathione, an important peptide in detoxification. Furthermore, it leads to chromosomal aberrations and seems to be associated with tissue damage and secondary compensatory hyperregeneration. More recently, the finding of considerable production of acetaldehyde by gastrointestinal bacteria was reported. Other mechanisms by which alcohol stimulates carcinogenesis include the induction of cytochrome P4502E1, associated with an enhanced activation of various procarcinogens present in alcoholic beverages, in association with tobacco smoke and in diets, a change in the metabolism and distribution of carcinogens, alterations in cell cycle behavior such as cell cycle duration leading to hyperregeneration, nutritional deficiencies such as methyl, vitamin A, folate, pyrridoxalphosphate, zinc and selenium deficiency, and alterations of the immune system, eventually resulting in an increased susceptibility to certain viral infections such as hepatitis B virus and hepatitis C virus. In addition, local mechanisms in the upper gastrointestinal tract and in the rectum may be of particular importance. Such mechanisms lead to tissue injury such as cirrhosis of the liver, a major prerequisite for hepatocellular carcinoma. Thus, all these mechanisms, functioning in concert, actively modulate carcinogenesis, leading to its stimulation.
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PMID:Alcohol and cancer. 975 43

Bacterial constituents and products of the bacterial metabolism pass from the gut lumen to the portal vein and may influence the homeostasis of the liver. Our aim is to examine whether DNA synthesis of human hepatocyte cell lines is affected by constituents of Escherichia coli species as well as by intracolonic products of bacterial fermentation that reach the liver via the portal vein. Supernatant solutions and bacterial cell fractions (containing either whole dead bacteria, cell walls, cytosol or non-soluble intracellular components) of E. coli K12 and of E. coli species from rat fecal flora were separated by multi-step centrifugation, French press, and microfiltration. The supernatant solution and the cell fractions were incubated with a human hepatoma cell line (Hep-G2) and with a cell line derived from non-malignant human liver cells (Chang cells) for 24 h. The cells were labeled with tritiated thymidine before processing to autoradiography. DNA synthesis was estimated by the labeling index (LI%). DNA synthesis was also estimated following incubation of Hep-G2 cells with short chain fatty acids (acetic, propionic, butyric and succinic acid), acetaldehyde, and ammonium chloride. Epidermal growth factor and a water extract of Helicobacter pylori were used as references. The fractions of E. coli from rat fecal flora containing cytosol and non-soluble intracellular components significantly increased the labeling index in both Hep-G2 and Chang cells (p < 0.05). In addition, the supernatant solution significantly increased the LI in Chang cells (p < 0.05). Epidermal growth factor increased the LI of Hep-G2 cells dose-dependently (p < 0.05). Butyric acid reduced DNA synthesis at 10(-4) M (p < 0.05). The highest doses of acetaldehyde were cytotoxic and reduced the LI. Escherichia coli species contain mitogenic factors to human hepatocytes. The mitogen(s) are present in the supernatant solution, in the cytosol and in non-soluble intracellular components. Butyrate, which is a product of bacterial fermentation of colonic substrates inhibit DNA synthesis in the hepatocyte cell lines. Our findings suggest that soluble mitogen(s) that diffuse from the microorganism to the outer environment, intracellular bacterial constituents, and products of the bacterial metabolism that reach the liver via the portal vein may influence the cell kinetic steady-state of hepatic cells.
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PMID:Butyrate inhibits and Escherichia coli-derived mitogen(s) stimulate DNA synthesis in human hepatocytes in vitro. 1023 92

Glutathione-doxorubicin (GSH-DXR) effectively induced apoptosis in rat hepatoma cells (AH66) at a lower concentration than DXR. After 24 h of drug treatment, DNA fragmentation of the cells was observed at the concentration of 1.0 microM DXR or 0.01 microM GSH-DXR. Increase in caspase-3 activity and DNA fragmentation were observed within 12 h and 15 h after treatment with either drug. Intracellular caspase-3 activity was increased in a dose-dependent manner after treatment with DXR or GSH-DXR, and caspase-3 activity correlated well with the ability to induce DNA fragmentation. When the cells were treated with either DXR or GSH-DXR for only 6 h, apoptotic DNA degradation and caspase-3 activation occurred 24 h after treatment. DNA fragmentation caused by these drugs was prevented completely by simultaneous treatment with the caspase-3 inhibitor, acetyl-Asp-Glu-Val-Asp-aldehyde (DEVD-CHO), at 10 microM. By contrast, DNA fragmentation was not prevented by the caspase-1 inhibitor, acetyl-Tyr-Val-Ala-Asp-aldehyde (YVAD-CHO), at the same concentration as DEVD-CHO, and caspase-1 was not activated at all by the treatment of AH66 cells with both DXR and GSH-DXR. These results demonstrate that DXR and GSH-DXR induce apoptotic DNA fragmentation via caspase-3 activation, but not via caspase-1 activation, and that GSH-DXR enhances the activation of caspase-3 approximately 100-fold more than DXR. Moreover, the findings suggested that an upstream apoptotic signal that can activate caspase-3 is induced within 6 h by treating AH66 cells with the drug.
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PMID:Caspase-3 activation during apoptosis caused by glutathione-doxorubicin conjugate. 1036 Jun 48

The polymorphism in the ALDH2 gene plays a central role in Asian alcohol hypersensitivity and has been associated with the risk for esophageal cancer. In the present study, we attempted to examine associations between the ADH2 and ALDH2 polymorphisms, alcohol drinking and hepatocellular carcinoma (HCC) development in a case-control study in Japan. One hundred and two patients with HCC (85 males and 17 females) and 125 control subjects (101 males and 24 females) were enrolled in the study. Higher cumulative amounts of alcohol consumption (drink-years of > or = 40 drinks/day x year) showed a significant association with HCC development (odds ratio, OR = 2.7; 95% CI = 1.3-5.5, adjusted for age and smoking). By contrast, we could find no association of the ALDH2 genotypes with HCC development (adjusted OR for ALDH2*1/*2 = 1.1; 95% CI = 0.6-2.1). Likewise, the ADH2 genotypes were not associated with HCC development (adjusted OR for ADH2*2/*2 = 0.8; 95% CI = 0.5-1.5). The present results do not support a contribution of acetaldehyde, an active metabolite of ethanol, to HCC development and rather indicate a direct involvement of ethanol in hepatocarcinogenesis.
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PMID:Relationship between alcohol drinking, ADH2 and ALDH2 genotypes, and risk for hepatocellular carcinoma in Japanese. 1073 10

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

Much progress has been made in the understanding of the pathogenesis of alcoholic liver disease, resulting in improvement of treatment. Therapy must include correction of nutritional deficiencies, while taking into account changes of nutritional requirements. Methionine is normally activated to S-adenosylmethionine (SAMe). However, in liver disease, the corresponding enzyme is depressed. The resulting deficiencies can be attenuated by the administration of SAMe but not by methionine. Similarly, phosphatidylethanolamine methyltransferase activity is depressed, but the lacking phosphatidylcholine (PC) can be administrated as polyenylphosphatidylcholine (PPC). Chronic ethanol consumption increases CYP2E1, resulting in increased generation of toxic acetaldehyde and free radicals, tolerance to ethanol and other drugs, and multiple ethanol-drug interactions. Experimentally, PPC opposes CYP2E1 induction and fibrosis. Alcoholism and hepatitis C infection commonly co-exist, with acceleration of fibrosis, cirrhosis, and hepatocellular carcinoma. PPC is being tested clinically as a corresponding antifibrotic agent. Available antiviral agents are contraindicated in the alcoholic. Anti-inflammatory agents, such as steroids, may be selectively useful. Finally, anticraving agents, such as naltrexone or acamprosate, should be part of therapy.
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PMID:Liver diseases by alcohol and hepatitis C: early detection and new insights in pathogenesis lead to improved treatment. 1126 19


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