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)

Aim of the study was to investigate the usefulness of two human derived hepatoma cell lines (HepG2 and Hep3B) for the detection of dietary and lifestyle related DNA-reactive carcinogens. Comparisons of the sensitivity of HepG2 cells of different origin towards benzo[a]pyrene (B(a)P) showed that strong differences exist in the induction of micronuclei (MN). The most sensitive was used for all further experiments, in which we investigated the effects of aflatoxin B(1) (AFB(1)), B(a)P, As(2)O(3), CdCl(2), 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), N-nitrosodimethylamine (NDMA), N-nitrosopyrrolidine (NPYR), 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), ethanol, acetaldehyde and caffeic acid in micronucleus (MN) tests. Dose dependent effects were detected in HepG2 with AFB(1) (0.2microM), CdCl(2) (2.2microM), As(2)O(3) (8.1microM), B(a)P (22.7microM), PhIP (35.7microM), NDMA (22.7mM), acetaldehyde (11.2mM) and ethanol (442.2mM). Numbers in parentheses indicate the C(D) values (concentration that induced a two-fold increase over the background). NNK and caffeic acid gave negative results under all conditions. In Hep3B cells, the effects were generally weaker. With PhIP, As(2)O(3) and NDMA negative results were obtained; with caffeic acid and NPYR marginal but significant induction of MN was observed. Enzyme measurements showed that both cell lines possess CYP1A1, glutathione-S-transferase (three-fold higher in HepG2) as well as N-acetyltransferase (NAT) 1 and sulfotransferases (SULT1A1 and SULT1A3; two- and seven-fold higher in HepG2); other cytochrome P450 enzymes (CYP1A2, 2B1, 2E1) and NAT2 were not detectable. The differences in the activities of the various enzymes may explain the contrasting results obtained in the MN experiments. Overall, our results indicate that the HepG2 line is more sensitive towards dietary genotoxins than Hep3B, and support the assumption that the HepG2/MN assay enables the detection of genotoxic carcinogens which give negative results in other currently used in vitro assays.
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PMID:Genotoxic effects of dietary and lifestyle related carcinogens in human derived hepatoma (HepG2, Hep3B) cells. 1522 90

Heavy alcohol consumption can damage various cells and organs partly through production of reactive oxygen species (ROS) and mitochondrial dysfunction. Treatment with antioxidants can significantly reduce the degree of damage. Despite well established roles of ROS in alcohol-induced cell injury, the proteins that are selectively oxidized by ROS are poorly characterized. We hypothesized that certain cysteinyl residues of target proteins are oxidized by ROS upon alcohol exposure, and these modified proteins may play roles in mitochondrial dysfunction. A targeted proteomics approach utilizing biotin-N-maleimide (biotin-NM) as a specific probe to label oxidized cysteinyl residues was employed to investigate which mitochondrial proteins are modified during and after alcohol exposure. Human hepatoma HepG2 cells with transduced CYP2E1 (E47 cells) were used as a model to generate ROS through CYP2E1-mediated ethanol metabolism. Following exposure to 100 mM ethanol for 4 and 8 h, the biotin-NM-labeled oxidized proteins were purified with agarose coupled to either streptavidin or monoclonal antibody against biotin. The purified proteins were resolved by two-dimensional gel electrophoresis and protein spots that displayed differential abundances were excised from the gel, in-gel digested with trypsin and analyzed for identity utilizing either matrix-assisted laser desorption-time of flight mass spectrometry or microcapillary reversed-phase liquid chromatography-tandem mass spectrometry. The results demonstrate that heat shock protein 60, protein disulfide isomerase, mitochondrial aldehyde dehydrogenases, prohibitin, and other proteins were oxidized after alcohol exposure. The identity of some of the proteins purified with streptavidin-agarose was also confirmed by immunoblot analyses using the specific antibody to each target protein. This method was also used to identify oxidized mitochondrial proteins in the alcohol-fed mouse liver. These results suggest that exposure to ethanol causes oxidation of various mitochondrial proteins that may negatively affect their function and contribute to alcohol-induced mitochondrial dysfunction and cellular injury.
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PMID:Identification of oxidized mitochondrial proteins in alcohol-exposed human hepatoma cells and mouse liver. 1544 75

Aldehyde oxidases are a family of highly related molybdo-flavoenzymes acting upon a variety of compounds of industrial and medical importance. We have identified aldehyde oxidase 1 (AOX1) as a 2,3,7,8-tetrachlorodibenzo-p-dioxin (dioxin) inducible gene in the mouse hepatoma cell line Hepa-1. AOX1 mRNA levels were not increased by dioxin in mutant derivatives of the Hepa-1 cell line lacking either functional aryl hydrocarbon receptor (AHR) or aryl hydrocarbon receptor nuclear translocator (ARNT) proteins, thus demonstrating that transcriptional induction of AOX1 in response to dioxin occurs through the AHR pathway. Dioxin induction of AOX1 mRNA was also observed in mouse liver. In addition, levels of AOX1 protein as well as those of aldehyde oxidase homologue 1 (AOH1), a recently identified homolog of AOX1, were elevated in mouse liver in response to dioxin. Employing an aldehyde oxidase specific substrate, AOX1/AOH1 activity was shown to be induced by dioxin in mouse liver. This activity was inhibited by a known inhibitor of aldehyde oxidases, and eliminated by including tungstate in the mouse diet, which is known to lead to inactivation of molybdoflavoenzymes, thus confirming that the enzymatic activity was attributable to AOX1/AOH1. Our observations thus identify two additional xenobiotic metabolizing enzymes induced by dioxin.
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PMID:Identification of aldehyde oxidase 1 and aldehyde oxidase homologue 1 as dioxin-inducible genes. 1566 68

Alcoholic fatty liver is the earliest and most common response of the liver to alcohol in heavy alcohol use, and it may be a precursor of more severe forms of liver injury. We and colleagues in our laboratory found that in two rat hepatoma cell lines, H4IIEC3 and McA-RH7777, ethanol markedly induced transcription of a sterol regulatory element-binding protein (SREBP)-regulated promoter through increased levels of mature SREBP-1 protein. Whereas inhibition of ethanol oxidation by 4-methylpyrazole blocked the effect, the aldehyde dehydrogenase inhibitor cyanamide enhanced the effect of ethanol in the hepatoma cells, supporting the idea that the effect is likely mediated by acetaldehyde. Consistent with these in vitro findings, consumption of a low-fat diet with ethanol by mice for 4 weeks resulted in a significant increase in the abundance of the mature (active) form of hepatic SREBP-1. Activation of SREBP-1 by ethanol feeding was associated with increased expression of lipogenic genes as well as the accumulation of triglyceride in the livers. Taken together, these findings seem to indicate that metabolism of ethanol increased hepatic lipogenesis by activating SREBP-1 and that this effect of ethanol may contribute to the development of alcoholic fatty liver. We and colleagues in our laboratory further studied the mechanisms of ethanol activation of SREBP-1 by identifying a new target of ethanol, adenosine 5'-monophosphate (AMP)-activated protein kinase. Our study results demonstrated that the effect of ethanol on SREBP-regulated promoter activation was mediated, at least in part, through inhibition of AMP-activated protein kinase. Consistent with this hypothesis, chronic ethanol feeding (4 weeks) resulted in a significantly reduced activity and protein level of AMP-activated protein kinase and increased acetyl coenzyme A carboxylase activity in the mouse livers.
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PMID:Molecular mechanisms of alcoholic fatty liver: role of sterol regulatory element-binding proteins. 1567 Jun 64

Hepatocellular carcinoma is the eighth most frequent cancer in the world, accounting for approximately 500,000 deaths per year. Unlike many malignancies, hepatocellular carcinoma occurs predominantly within the context of known risk factors, with hepatic cirrhosis being the most common precursor to the development of hepatocellular carcinoma. After ethanol ingestion, the liver represents the major site of metabolism. Ethanol metabolism by alcohol dehydrogenase leads to the generation of acetaldehyde and free radicals that bind rapidly to numerous cellular targets, including components of cell signaling pathways and DNA. In addition to direct DNA damage, acetaldehyde depletes glutathione, an antioxidant involved in detoxification. Chronic ethanol abuse leads to induction of hepatocyte microsomal cytochrome P450 2E1, an enzyme that metabolizes ethanol to acetaldehyde and, in doing so, causes further free radical production and aberrant cell function. Cytochrome P450 2E1-dependent ethanol metabolism is also associated with activation of procarcinogens, changes in cell cycle, nutritional deficiencies, and altered immune system responses. The identification of oxidative stress in mediating many deleterious effects of ethanol in the liver has led to renewed interest in the use of dietary antioxidants as therapeutic agents. Included in this group are S-adenosyl-L-methionine and plant-derived flavanoids.
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PMID:Alcohol and liver cancer. 1605 81

Mitochondrial aldehyde dehydrogenase (ALDH2) is responsible for the metabolism of acetaldehyde and other toxic lipid aldehydes. Despite many reports about the inhibition of ALDH2 by toxic chemicals, it is unknown whether nitric oxide (NO) can alter the ALDH2 activity in intact cells or in vivo animals. The aim of this study was to investigate the effects of NO on ALDH2 activity in H4IIE-C3 rat hepatoma cells. NO donors such as S-nitrosoglutathione (GSNO), S-nitroso-N-acetylpenicillamine, and 3-morpholinosydnonimine significantly increased the nitrite concentration while they inhibited the ALDH2 activity. Addition of GSH-ethylester (GSH-EE) completely blocked the GSNO-mediated ALDH2 inhibition and increased nitrite concentration. To directly demonstrate the NO-mediated S-nitrosylation and inactivation, ALDH2 was immunopurified from control or GSNO-treated cells and subjected to immunoblot analysis. The anti-nitrosocysteine antibody recognized the immunopurified ALDH2 only from the GSNO-treated samples. All these results indicate that S-nitrosylation of ALDH2 in intact cells leads to reversible inhibition of ALDH2 activity.
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PMID:Inhibition of mitochondrial aldehyde dehydrogenase by nitric oxide-mediated S-nitrosylation. 1624 27

Chronic alcohol consumption is associated with an increased risk for upper aerodigestive tract cancer and hepatocellular carcinoma. Increased acetaldehyde production via alcohol dehydrogenase (ADH) has been implicated in the pathogenesis. The allele ADH1C*1 of ADH1C encodes for an enzyme with a high capacity to generate acetaldehyde. So far, the association between the ADH1C*1 allele and alcohol-related cancers among heavy drinkers is controversial. ADH1C genotypes were determined by polymerase chain reaction and restriction fragment length polymorphism in a total of 818 patients with alcohol-associated esophageal (n=123), head and neck (n=84) and hepatocellular cancer (n=86) as well as in patients with alcoholic pancreatitis (n=117), alcoholic liver cirrhosis (n=217), combined liver cirrhosis and pancreatitis (n=17) and in alcoholics without gastrointestinal organ damage (n=174). The ADH1C*1 allele and genotype ADH1C*1/1 were significantly more frequent in patients with alcohol-related cancers than that in individuals with nonmalignant alcohol-related organ damage. Using multivariate analysis, ADH1C*1 allele frequency and rate of homozygosity were significantly associated with an increased risk for alcohol-related cancers (p<0.001 in all instances). The odds ratio for genotype ADH1C*1/1 regarding the development of esophageal, hepatocellular and head and neck cancer were 2.93 (CI, 1.84-4.67), 3.56 (CI, 1.33-9.53) and 2.2 (CI, 1.11-4.36), respectively. The data identify genotype ADH1C*1/1 as an independent risk factor for the development of alcohol-associated tumors among heavy drinkers, indicating a genetic predisposition of individuals carrying this genotype.
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PMID:Alcohol dehydrogenase 1C*1 allele is a genetic marker for alcohol-associated cancer in heavy drinkers. 1628 84

Steroid and xenobiotic receptor (SXR) or human pregnane X receptor (hPXR) dimerizes with retinoid X receptor (RXR) and regulates the transcription of genes encoding xenobiotic-metabolizing enzymes such as CYP3A4. Rifampin, the classical activator of CYP3A4, binds to SXR directly. It is unclear whether various natural and synthetic retinoids can regulate the expression of CYP3A4. To evaluate the effects of retinoids on the RXR/SXR-mediated pathway, transient transfection assays were performed on both CV-1 and human hepatoma Huh7 cells using a reporter construct containing multiple RXR/SXR consensus binding elements (an everted repeat with a 6-nucleotide spacer, ER-6). The results revealed that eight out of 13 retinoids screened significantly induced the RXR/SXR-mediated pathway in Huh7 cells. At an equal molar concentration, the acid forms (9-cis-RA, 13-cis-RA, and all-trans-RA) or aldehyde, the direct precursor of acid (9-cis-retinal and 13-cis-retinal), exhibited a greater or similar potency than rifampin. Depending on the ligands, RXR may serve as a silent or an active partner of SXR. Additionally, retinoids can increase CYP3A4 enzyme activity in Huh7 cells. To further evaluate the potential drug-drug interactions, which may be caused by retinoids, Huh7 cells were pretreated with 9-cis-RA and followed by acetaminophen. We showed that 9-cis-RA enhanced the covalent binding of N-acetyl-p-quinoneimine, a toxic intermediate of acetaminophen produced by phase I enzymes oxidation. This result suggested that drug-drug interaction might occur between 9-cis-RA and acetaminophen in human liver cells. Taken together, retinoids activate the RXR/SXR-mediated pathway and regulate the expression of CYP3A4. Thus, retinoids potentially can cause drug-drug interactions when they are administered with other CYP3A4 substrates.
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PMID:Retinoids activate the RXR/SXR-mediated pathway and induce the endogenous CYP3A4 activity in Huh7 human hepatoma cells. 1663 23

The deficiency in activity of aldehyde dehydrogenase-2 (ALDH2), commonly found in Asians, is due to a mutation at position 487 in exon 12, encoded by the ALDH2*2 allele, which is a crucial factor for deficient ability to acetaldehyde (AcH) oxidation. In addition to this locus, polymorphism in -361 G/A mutation of this gene at 5'flanking region, commonly found in multi-racial populations, is one of the suggestive polymorphisms which may affect on the enzyme activity because it has been reported to affect on the transcriptional activity in hepatoma cells. We aimed to examine the individual differences in alcohol metabolism in Japanese population based on the genotypes of both ALDH2 exon 12 and -361 G/A promoter region. Following genotyping of 2 loci, subject groups based on the promoter genotype was defined as variant A carrier (A+; A/A and G/A) or not (A-; G/G). Under the condition with 0.4 g/kg body weight of alcohol ingestion, significant differences in AcH peak levels, that reached at 30 or 60 minutes in most subjects, was not detected between promoter A+ and A- groups both in exon 12 ALDH2*1/*1 and ALDH2*1/*2 subjects. Furthermore, we developed a real-time RT-PCR method to detect and quantitate the ALDH2 mRNA levels in easily accessible peripheral blood leukocytes (PBLs) to examine whether this promoter mutation affects on the amount of ALDH2 mRNA in normal human tissue at pre- and post-alcohol ingestion phase in ALDH2*1/*1 subjects. Significant increase of mRNA was observed only in A- group at 2 hours after alcohol ingestion. Maximal changing rates of mRNA in PBLs within 3 hours after alcohol intake were +48 % and +17 % in A and A' groups, respectively. These results suggest that the individual differences in ALDH2 enzyme activity may be intricately regulated by the common polymorphisms in these two loci in Asian populations.
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PMID:Effect of -361 G/A polymorphism of aldehyde dehydrogenase-2 gene on alcohol metabolism and its expression in human peripheral blood leukocytes. 1673 78

The aryl hydrocarbon receptor (AhR) is a ligand-activated basic-helix-loop-helix transcription factor that binds polyaromatic hydrocarbons (PAH), such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), and mediates their toxicity. Binding of PAH to AhR in the cytoplasm triggers a poorly defined transformation step of the receptor into a nuclear transcription factor. In this study, we show that the calcium-dependent cysteine protease calpain plays a major role in the ligand-induced transformation and signaling of AhR. Fluorescence imaging measurements showed that TCDD treatment elevates intracellular calcium, providing the trigger for calpain activation, as measured toward t-butoxycarbonyl-Leu-Met-chloromethylaminocoumarin, a calpain-specific substrate. Inhibition of calpain activity by the N-benzyloxycarbonyl-Val-Phe-aldehyde (MDL28170) blocked the TCDD-induced nuclear translocation of AhR in Hepa1c1c7 mouse hepatoma cell line. Treatment of the human metastatic breast carcinoma cell line MT-2 with MDL28170 and 3-(4-iodophenyl)-2-mercapto-(Z)-2-propenoic acid (PD 150606), two calpain-selective inhibitors, completely abolished the TCDD-induced transactivation of AhR as assessed by transcription of CYP1A1 gene. Previous studies have established that after TCDD-induced transactivation, the AhR undergoes a massive depletion; we show here that selective calpain inhibitors can block this step, which suggests that the ligand-induced down-regulation of the AhR is calpain-dependent. The data presented support a major role for calpain in the AhR transformation, transactivation, and subsequent down-regulation, and provide a possible explanation for many of the reported phenomena of ligand-independent activation of AhR.
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PMID:Calpain mediates the dioxin-induced activation and down-regulation of the aryl hydrocarbon receptor. 1718 82


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