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)

In vitro drug metabolism in the Hartley guinea pig was compared with that in two inbred guinea pig strains used as carriers for the line 10 hepatoma. We observed minor differences in enzyme specific activity among the three strains. Three weeks after intradermal inoculation of Strain 2 guinea pigs with line 10 hepatoma cells, cytochrome P450 levels and aminopyrine demethylase activity were significantly decreased. Seven to 10 days after inoculation with the ascites form of the tumor, the activities of aniline and biphenyl hydroxylases, p-aminobenzoic acid N-acetyltransferase, and dichloronitrobenzene glutathione S-aryltransferase, in addition to those of cytochrome P450 and aminopyrine N-demethylase, were probably also described.
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PMID:Effect of strain differences and tumor presence on microsomal drug metabolism in the guinea pig: brief communication. 20 Jul 61

Many arylamine and hydrazine drugs and xenobiotics are acetylated by N-acetyltransferase (NAT), a cytosolic enzymic activity which has a wide tissue distribution. Humans can be classified as either fast or slow acetylators on the basis of their ability to metabolise isoniazid or sulphamethazine. These are termed polymorphic substrates. The acetylation of other compounds does not vary amongst individuals, e.g., p-aminobenzoic acid, and are termed monomorphic substrates. NAT from human hepatic and non-hepatic tissues, viz., (i) liver, (ii) the hepatoma cell line HepG2, (iii) tonsil lymphocytes and (iv) the monocytic cell line U937 have been compared with respect to substrate specificity towards polymorphic and monomorphic substrates. The chromatographic and centrifugation behaviour of NAT from these sources has also been investigated. NAT from liver shows 2-fold greater activity towards sulphamethazine than towards p-aminobenzoic acid as substrate. All other cell types tested show at least 70-fold greater activity with p-aminobenzoic as substrate compared to sulphamethazine. NAT from HepG2 cells, U937 cells and tonsil lymphocytes migrates as a single peak during ion-exchange chromatography, whereas the liver NAT activity is separated into two peaks. NAT in HepG2 cells resembles extra-hepatic tissue NAT rather than NAT in liver. HepG2 cells do not therefore represent a good in vitro model for investigation of human metabolism of arylamines or hydrazines. The molecular weight of NAT from U937 cells has been determined by a combination of sucrose density gradient centrifugation and gel filtration to be 31,600 +/- 1200 daltons.
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PMID:Drug metabolising N-acetyltransferase activity in human cell lines. 201 83

This study was aimed at monitoring N-acetyltransferase activities of continuous cell lines, which differ in their sensitivity to the toxic effects of nitroaromatic compounds. Transferase activities were measured toward the acetyl acceptors sulfamethazine and p-aminobenzoic acid in partially purified preparation of cytosols. Cell lines such as hamster V79, BHK, rat hepatoma H4IIEC3G- or fibroblast 208F, which are sensitive to 1,6-dinitropyrene (1,6-DNP), possess high transferase activities ranging from 120-270 nmol/min x mg protein. In contrast, human lung cells NCI-H322, mouse and rat hepatoma cells BW1J and H5, respectively, which are resistant to 1,6-DNP contain no or low transferase activity of less than 15 nmol/min x mg. There was no apparent correlation between 1,6-DNP sensitivity and acetyltransferase levels in a few cell lines, e.g. rat hepatoma HTC, 2sFou and 5L, which express intermediate transferase activities ranging from 25-50 nmol/min x mg protein. The results suggest that acetylation is an essential step in activating 1,6-DNP to toxic products in mammalian cells.
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PMID:Arylamine N-acetyltransferase activities in cell lines of mouse, rat, hamster and man differing in their sensitivity to 1,6-dinitropyrene. 224 42

Many arylamine and hydrazine drugs and xenobiotics are acetylated by liver N-acetyltransferase (NAT; EC 2.3.1.5). Two loci, mnat and pnat, encode the enzymes designated monomorphic and polymorphic NAT (mNAT and pNAT) respectively. These isoenzymes have different substrate specificities. In addition, at the polymorphic locus a diversity of alleles is found, which differ by specific point mutations that may or may not result in amino acid substitutions. These point mutations result in the 'slow' acetylation of substrates of pNAT. The substrates for NAT include carcinogenic arylamines. Susceptibility to bladder cancer has been related to slow acetylation. NAT has been characterized in immortalized human cell lines to assess their use in studies of the metabolism or arylamines in vitro. A monocytic cell line (U937) and two hepatoma cell lines of parenchymal lineage (HepG2 and Hep3B) have been shown to catalyse acetylation of substrates of mNAT but do not acetylate sulphamethazine, a substrate specific for pNAT. Using PCR to amplify the alleles of pNAT, followed by restriction-enzyme digestion of the product, the cell lines have been genotyped: U937 cells are homozygous slow acetylators (S1a/S1a) and HepG2 cells are heterozygous slow acetylators (S1a/S2). Transcription of pnat was confirmed in the hepatoma cell lines, by amplification of cDNA generated from these cells. In addition, splicing of mRNA specific for pNAT has been demonstrated by using a primer which anneals to a region in the 5' promoter region. Unlike the hepatoma cell lines, in U937 cells the pNAT gene is not transcribed. However, transcription of mnat was shown to occur in all three cell lines.
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PMID:Arylamine N-acetyltransferase activity in human cultured cell lines. 839 14

The arylamine N-acetyltransferase (NAT2) is a polymorphic enzyme which is expressed in the liver in a genotype-determined manner. NAT2 is involved in activation and inactivation of carcinogens through N-acetylation. We studied the role of this polymorphism in the development of hepatocellular carcinoma (HCC). One hundred consecutive patients diagnosed for HCC and 258 healthy volunteers were studied for NAT2 genotype. The occurrence of seven enzyme-inactivating and silent point mutations in the coding region of the NAT2 gene was studied by mutation-specific PCR amplification. An excess of subjects homozygous for NAT2 loss of function alleles was observed among patients with HCC (68% vs 53.9% controls). The relationship between the slow acetylator NAT2 genotype and HCC risk is more pronounced in patients lacking serum HBV and HCV markers. The additional determination of alleles of the cytochrome P450 2D6 (CYP2D6) gene in the same subjects confirmed our previous findings that subjects with two active CYP2D6 genes are at increased risk of developing HCC. The genetic polymorphism of NAT2 is a relevant factor in the risk for developing HCC (inverse odds ratio slow vs rapid = 1.8; 95% CI 1.1-3.0). The inverse odds ratio for subjects with two risk genotypes (two defect NAT2 genes and two or more active CYP2D6 genes) is 2.6 (95% CI 1.6-4.4) for all patients with HCC, and 5.6 (95% CI 1.4-33.3) for patients without serum viral markers.
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PMID:Increased risk for hepatocellular carcinoma in NAT2-slow acetylators and CYP2D6-rapid metabolizers. 901 99

The present study has determined the effects of 6-nitrochrysene (6-NC) on human cytochrome P450-dependent monooxygenases in human hepatoma HepG2 cells. Treatment of HepG2 cells with 6-NC increased the activities of microsomal benzo[a]pyrene hydroxylase, 7-ethoxycoumarin and 7-ethoxyresorufin O-deethylases, cytosolic glutathione S-transferase and N-acetyltransferase, and S9 metabolic activation of 6-NC in the Ames mutagenicity test. Immunoblot and RNA blot analyses revealed that 6-NC induced CYP1A1 protein and mRNA levels in the hepatoma cells. Nuclear transcription assay demonstrated that 6-NC increased the transcription rate of CYP1A1 gene in HepG2 cells. Treatment of human lung carcinoma NCI-H322 cells with 6-NC increased benzo[a]pyrene hydroxylase activity and CYP1A1 protein and mRNA levels. These results demonstrate that 6-NC is an inducer of human CYP1A1 and the induction occurs at a transcriptional level in HepG2 cells. The ability of 6-NC to induce liver and lung CYP1A1 may be an important factor to consider in assessing 6-NC metabolism and toxicity in humans.
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PMID:Induction of cytochrome P450 1A1 in human hepatoma HepG2 cells by 6-nitrochrysene. 1103 35

Genetic polymorphisms of the carcinogen-metabolizing enzymes cytochrome P450 (CYP), glutathione S-transferase (GST) M1 and N-acetyltransferase (NAT2) as well as p53 polymorphisms have been studied experimentally as susceptibility markers for hepatocellular carcinoma development in hepatocellular carcinoma cell lines and in mouse hepatocellular carcinomas. In addition, these susceptibility markers have been studied in hepatocellular carcinoma patients, in the context of coexisting alcohol consumption, smoking and/or HBV infection. To date, there is no clear evidence that susceptibility markers have an overall impact on hepatocarcinogenesis, but in subgroups of individuals, such as smokers, susceptibility markers are emerging indicators for hepatocellular carcinoma risk definition.
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PMID:Hepatocellular carcinoma: susceptibility markers. 1122 Jun 63

The inhibition ofarylamine N-acetyltransferase (NAT) activity by norcantharidin (NCTD), the demethylated form of cantharidin, in human hepatocellular carcinoma HepG2 cells was investigated. By using high performance liquid chromatography, NAT activity on acetylation of 2-aminofluorene (AF) and p-aminobenzoic acid (PABA) were examined. Two assay systems were performed, one with cellular cytosols, the other with intact HepG2 cell suspensions. The NAT activity in HepG2 cell line was inhibited by norcantharidin in a dose-dependent manner in both types of examined systems: i.e. the greater the concentration of norcantharidin in the reaction, the greater the inhibition of NAT activities. This report is the first to show that norcantharidin has an inhibitory effect on NAT activity in HepG2 cell.
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PMID:Effect of norcantharidin on N-acetyltransferase activity in HepG2 cells. 1132 74

This article describes the development and use of assay models in vitro (genotoxicity assay with genetically engineered cells and human hepatoma (HepG2) cells) and in vivo (genotoxicity and short-term carcinogenicity assays with rodents) for the identification of dietary constituents which protect against the genotoxic and carcinogenic effects of heterocyclic aromatic amines (HAs). The use of genetically engineered cells expressing enzymes responsible for the bioactivation of HAs enables the detection of dietary factors that inhibit the metabolic activation of HAs. Human derived hepatoma (HepG2) cells are sensitive towards HAs and express several enzymes [glutathione S-transferase (GST), N-acetyltransferase (NAT), sulfotransferase (SULT), UDP-glucuronosyltransferase (UDPGT), and cytochrome P450 isozymes] involved in the biotransformation of HAs. Hence these cells may reflect protective effects, which are due to inhibition of activating enzymes and/or induction of detoxifying enzymes. The SCGE assay with rodent cells has the advantage that HA-induced DNA damage can be monitored in a variety of organs which are targets for tumor induction by HAs. ACF and GST-P(+) foci constitute preneoplastic lesions that may develop into tumors. Therefore, agents that prevent the formation of these lesions may be anticarcinogens. The foci yield and the sensitivity of the system could be substantially increased by using a modified diet. The predictive value of the different in vitro and in vivo assays described here for the identification of HA-protective dietary substances relevant for humans is probably better than that of conventional in vitro test methods with enzyme homogenates. Nevertheless, the new test methods are not without shortcomings and these issues are critically discussed in the present article.
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PMID:Development and application of test methods for the detection of dietary constituents which protect against heterocyclic aromatic amines. 1262 16

In the multifactorial aetiology of hepatocellular carcinoma (HCC), an association and interaction between genetic polymorphisms of xenobiotic metabolizing enzymes, lifestyle factors, and cancer risk has been postulated. N-acetyltransferase (NAT2) is involved in the metabolic activation and detoxification of aromatic amines. Aromatic amines are potential hepatocarcinogens in humans. In the present study, we investigated if genetic NAT2 polymorphism is related to HCC. Genotyping of NAT2 was performed in 70 HCC patients and 87 controls using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) analysis. The results of this investigation show that 46 out 70 HCC patients (65.7%) and 50 out of 87 controls (57.5%) were of the slow acetylator genotypes. The frequency of distribution of slow and rapid acetylators (genotypes) was not significantly different between cases and controls (p > 0.05). Slow acetylator genotypes were not associated with a significantly increased HCC risk (odds ratio, 1.4; 95% confidence interval, 0.74-2.72). A significant association between NAT2 genetic polymorphism and HCC was observed among smokers. Slow acetylator genotypes significantly increased the HCC risk in cigarette smokers (odds ratio, 3.5; 95% confidence interval, 1.38-9.05). Our results suggest that genetic NAT2 polymorphism may play a role in lifestyle factors-related hepatocarcinogenesis. NAT2 activity may be particulary critical in smoking related hepatocarcinogenesis.
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PMID:Impact of N-acetyltransferase polymorphism (NAT2) in hepatocellular carcinoma (HCC)--an investigation in a department of surgical medicine. 1287 50


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