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)

Ingestion of aflatoxin B1 (AFB1) represents a major risk factor in the aetiology of human hepatocellular carcinoma. In the rat, the harmful effects of AFB1 can be prevented by the administration of certain drugs which induce hepatic detoxification enzymes. We have previously shown that treatment of rats with the chemoprotector ethoxyquin (EQ) results in a marked increase in expression of the Alpha-class glutathione S-transferase (GST) Yc2 subunit which has high activity towards AFB1-8,9-epoxide [Hayes, Judah, McLellan, Kerr, Peacock and Neal (1991) Biochem. J. 279, 385-398]. To allow an assessment of whether the increased expression of GST Yc2 represents a general adaptive resistance mechanism to chemical stress, that is invoked by both chemoprotectors and carcinogens, we have examined the effects of EQ, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), phenobarbital (PB), AFB1, 3-methylcholanthrene (3-MC) and clofibrate on the AFB1-glutathione-conjugating activity and the GST subunit levels in rat liver. In addition, the effect of these drugs on the hepatic levels of an aldehyde reductase (AFB1-AR) that metabolizes the cytotoxic dialdehydic form of AFB1 has been studied as this enzyme also appears to be important in chemoprotection. Administration of the antioxidants EQ, BHA or BHT, as well as PB, led to a marked increase in levels of the GST Yc2 subunit in rat liver, and this increase coincided with a substantial rise in the GST activity towards AFB1-8,9-epoxide; neither AFB1, 3-MC nor clofibrate caused induction of Yc2 or any of the GST subunits examined. Among the xenobiotics studied, EQ was found to be the most effective inducing agent for the Yc2 subunit as well as Yc1, Yb1 and Yf. However, PB was equally as effective as EQ in increasing levels of the Ya-type subunits, although it was not found to be as potent an inducer of the other GST subunits, including Yc2. In addition to induction of GST, EQ caused a substantial increase in the hepatic content of AFB1-AR. Both BHA and BHT were also able to induce this enzyme but, by contrast, PB was found to be a poor inducer of AFB1-AR. AFB1, 3-MC and clofibrate were unable to serve as inducers of this reductase. The presence of Alpha-class GST, including the Yc2 subunit, was examined in various rat tissues. Constitutive expression of Yc2 was found in the epididymis at levels comparable with that observed in the liver from EQ-treated rats.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Regulation of aflatoxin B1-metabolizing aldehyde reductase and glutathione S-transferase by chemoprotectors. 819 22

4-Hydroxynonenal (4-HNE), produced during the oxidative lipid breakdown of biological membranes, modulates various biochemical processes in normal liver and in hepatoma cells. It is very probable that the effects of 4-HNE are related to the quantity formed in the cells and to the cells' ability to metabolize it. Aldehyde catabolism takes place within the cells through oxidative and reductive enzymes, and through conjugation with intracellular glutathione. In this paper, the various enzymatic pathways involved in the metabolism of 4-HNE were studied in normal hepatocytes and in hepatoma cells. The hepatocyte pathway undergoes a complex variety of change during neoplastic transformation. In hepatoma cells, generally, 4-HNE metabolism was due mainly to aldehyde dehydrogenases, whereas in normal hepatocytes 4-HNE metabolism was mainly due to alcohol dehydrogenase and glutathione-S-transferase. The increase in oxidative enzymes compared to normal tissue was not the same in all types of hepatoma: in HTC hepatoma cells, the enzyme levels were considerably higher; in AH-130 hepatoma cells of Yoshida, they were lower in subcellular particles and similar in the cytosol. Indeed, consumption of externally-added 4-HNE in hepatoma cells was proportional to their content of 4-HNE metabolizing enzymes.
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PMID:Ability of different hepatoma cells to metabolize 4-hydroxynonenal. 832 85

Alcohol dehydrogenase isoenzymes were isolated from the liver of patients with hepatoma and healthy control individuals. Whereas only a single form of the enzyme was obtained in healthy control liver, two distinct forms of the enzyme were found in hepatoma liver. These two forms were named AD-I and AD-II according to their elution pattern in CM-cellulose chromatography and mobility towards the anode in polyacrylamide gel electrophoresis. Both isoenzymes resembled normal liver enzyme with respect to their molecular properties. However, the two forms had distinct kinetic properties, although AD-I had some properties similar to the normal liver enzyme. The Km values of AD-I for ethanol, n-butanol and m-nitrobenzyl alcohol were 61 microM, 90 microM and 292 microM, respectively, as against the values for AD-II which were 473 microM, 100 microM and 60 microM for the respective substrates. Pyrazole inhibited the activity of AD-II but not that of AD-I. These kinetic properties of alcohol dehydrogenase in patients with hepatoma could be of clinical importance particularly in the tropics where the disease is prevalent.
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PMID:Purification and catalytic properties of liver alcohol dehydrogenase isoenzymes in patients with hepatoma in Nigeria. 838 33

Several enzymes metabolize the toxic aldehydes produced during lipid peroxidation, such as 4-hydroxynonenal. During carcinogenesis induced by diethylnitrosamine in rat liver, an increase in aldehyde dehydrogenase, in comparison with normal liver, has already been shown. This paper demonstrates that, although to a lesser extent than aldehyde dehydrogenase, aldehyde reductase and glutathione-S-transferase also increase during carcinogenesis. Of the latter two enzymes, aldehyde reductase increases more markedly in a progressive fashion during the months of development of nodules and hepatoma. The increase of enzymes able to metabolize 4-hydroxynonenal, as well as other aldehydes, is certainly important in protecting tumour cells against cytotoxic effect of aldehydes.
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PMID:Glutathione-S-transferase, alcohol dehydrogenase and aldehyde reductase activities during diethylnitrosamine-carcinogenesis in rat liver. 844 90

The mouse alcohol dehydrogenase gene, Adh-1, is expressed in a tissue-specific manner. We examined the promoter activity of a series of 5' deletions extending from bp -473 to -47 and demonstrated that there are positive regulatory elements between bp -229 and +54 and a negative regulatory element between bp -323 and -229. To identify the sequence of the negative regulatory element, gel retardation and DNase I footprint assays were performed using nuclear proteins from mouse liver and from a hepatoma cell line, H4IIE-C3. A specific protein-binding site covered bp -324 and -297. Within this region, we identified sites of close protein-DNA contact by methylation interference assays, located in the sequence TGGAAGTTTCAGGTT (nt -316 to -302). Site-directed mutagenesis of four protein-DNA contact sites within this sequence eliminated the specific protein-DNA binding, assayed by gel retardation, and restored expression of Adh-1 in transient transfection assays to the levels seen when the entire region containing the negative element was deleted. Thus, we have identified a negative regulatory element within the Adh-1 promoter. No homology was found between this negative element and other regulatory elements, suggesting that this is a novel negative element.
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PMID:A novel negative element in the promoter of the mouse alcohol dehydrogenase gene Adh-1. 848 90

Three human alcohol dehydrogenase genes, ADH1, ADH2, and ADH3, were formed by tandem duplications and have diverged in their tissue-specific and developmental expression. Their proximal promoters remain 80-84% identical in sequence, approximately the same degree of identity as at synonymous sites in the coding regions of these three genes. To understand the evolution of tissue specificity, gene expression must be studied in many different cells and tissues. A systematic comparison of their promoters reveals the effects of subtle sequence differences on the binding of nuclear proteins to their cis-acting elements. There are differences in the affinity with which some proteins are bound to altered sites including C/EBP sites, USF/MLTF sites, and the G3T site (which binds Sp1). There are also differences in the sites that are occupied, e.g. CTF/NFI-related sites. These sequence differences are reflected in differences in gene expression in three cell lines. In H4IIE-C3 hepatoma cells, the ADH1 promoter was more active than the ADH2 promoter, and the ADH3 promoter was nearly nonfunctional. In HeLa cells, both ADH1 and ADH2 promoters directed expression; again the ADH3 promoter was extremely weak. None of the three promoters had much activity in CV-1 cells. Coexpression of C/EBP alpha greatly stimulated expression of the ADH1 promoter in HeLa cells and in CV-1 cells, but only weakly stimulated expression in H4IIE-C3 cells. The stimulation of the ADH1 promoter by C/EBP alpha was comparable to that of ADH2, despite the weaker binding to the C/EBP sites that flank the TATA box in ADH1. The ADH3 promoter was not greatly stimulated by C/EBP alpha, despite good binding of C/EBP alpha. These results demonstrate that small differences in the cis-acting elements affect affinity of binding by transcription factors and the pattern of gene expression.
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PMID:Gene expression in a young multigene family: tissue-specific differences in the expression of the human alcohol dehydrogenase genes ADH1, ADH2, and ADH3. 863 48

We examined age-related changes in the protein and the mRNA expression of aldose reductase in livers of Long-Evans with a cinnamon-like color (LEC) rats, which develop hereditary hepatitis and hepatoma with aging, using Long-Evans with an agouti color rats as controls. The levels of the protein and mRNA of aldose reductase increased after 20 weeks, at the stage of acute hepatitis, and were maintained at 60 weeks of age, while those of aldehyde reductase seemed to be constant at all ages. The expression of aldose reductase was marked in cancerous lesions in hepatoma-bearing LEC rat liver compared to uninvolved surrounding tissues. These results indicated that elevation of aldose reductase accompanied hepatocarcinogenesis and may be related to the acquisition of immortality of the cancer cells through detoxifying cytotoxic aldehyde compounds.
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PMID:Induction of aldose reductase gene expression in LEC rats during the development of the hereditary hepatitis and hepatoma. 864 63

Expression of the class I alcohol dehydrogenase (ADH) gene in the rat hepatoma microcell hybrid cell line, 11-3, was examined. The steady-state level of ADH mRNA in 11-3 was approximately 2-fold higher than that or rat liver and Fao, the parental cell line of 11-3. Removal of steroid hormones by activated charcoal from the serum in which 11-3 cells were maintained resulted in a significant decrease in the level of ADH transcript. Dexamethasone at a concentration of 1 muM increased the ADH mRNA content in 11-3 in a time-dependent fashion, up to 48 hr after its addition to cells that had first been deprived of steroid hormones. In addition, levels of ADH transcript in cells treated with dexamethasone increased in a dose-dependent manner, and the concentration of dexamethasone required to achieve half-maximal activation was 5 nM. By using the techniques of reverse transcription and polymerase chain reaction, and by taking advantage of a restriction polymorphism present between the rat and mouse ADH cDNA, we found that 11-3 contained both the rat and mouse class I ADH transcripts, although the rat sequence accounted for the great majority. Moreover, levels of both rat and mouse class I ADH transcripts increased in a similarly time-dependent manner in cells treated with dexamethasone. These results indicate that expression of class I ADH gene in 11-3 is high and is regulated by glucocorticoids, making the cell line an excellent model for the in vitro study of ADH expression.
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PMID:The class I alcohol dehydrogenase gene is glucocorticoid-responsive in the rat hepatoma microcell hybrid cell line, 11-3. 874 6

Expression of the serum albumin gene is extinguished in rat hepatoma microcell hybrids that retain mouse chromosome 1. These data define a trans-dominant extinguisher locus, Tse-2, on mouse chromosome 1. To localize the human TSE2 locus, we prepared and characterized rat/human microcell hybrids that contained either human chromosome 1 or chromosome 2, the genetic homologues of mouse chromosome 1. Rat hepatoma microcell hybrids retaining a derivative human chromosome 1 [der 1 t(1;17)(p34.3;q11.2)] expressed their serum albumin genes at levels similar to those of parental hepatoma cells. In contrast, microcell transfer of human chromosome 2 into rat hepatoma recipients produced karyotypically heterogeneous collections of hybrid clones, some of which displayed dramatic albumin extinction phenotypes. For example, albumin mRNA levels in several extinguished microcell hybrids were reduced at least 500-fold, similar to albumin mRNA levels in hepatoma x fibroblast whole-cell hybrids. Expression of several other liver genes, including alpha 1-antitrypsin, aldolase B, alcohol dehydrogenase, and phosphoenolpyruvate carboxykinase, was also affected in some of the microcell hybrids, but expression of these genes was not concordant with expression of albumin. Hybrid segregants were prepared from the albumin-extinguished hybrids, and reexpression of albumin mRNA and protein was observed in sublines that had lost or fragmented human chromosome 2. Finally, expression of mRNAs encoding the liver-enriched trans activators HNF-1, HNF-4, HNF-3 alpha, and HNF-3 beta was not affected in any of the chromosome 2-containing hybrids. These data define and map a genetic locus on human chromosome 2 that extinguishes albumin gene expression in trans, and they suggest that TSE2-mediated extinction is independent of HNF-1, -4, -3 alpha, and -3 beta expression.
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PMID:Extinction of albumin gene expression in a panel of human chromosome 2 microcell hybrids. 883 17

Upon birth, the liver acquires new functions as a result of the initiation of expression of key enzymes. One example is the initiation of gluconeogenesis which depends on the induced appearance of phosphoenolpyruvate carboxykinase (P-pyruvate-CK) at birth. To characterize other genes that undergo such regulation, a differential screening was performed on a cDNA library from well-differentiated hepatoma cells. The pattern of tissue-specific and developmental-specific expression was determined for seven genes. Three clones, out of which two encode for the known genes alcohol dehydrogenase class I (ADH) and phenylalanine 4-monooxygenase (PAH) and a new gene (clone 116-3), exhibited a pattern of expression similar to that of the P-pyruvate-CK gene, i.e. their expression was liver and kidney specific and induced in the liver upon birth. Determination of the sequence of clone 116-3 revealed that it belonged to the UDP-glucuronosyltransferases type 2 (UGT2) family and thus was named UGT2B-rH4. To examine whether expression of the various genes could be prematurely induced by hormones in the fetal liver, either high levels of cAMP or low levels of insulin were induced in utero. The results demonstrated that cAMP induced a marked expression only of the genes for P-pyruvate-CK and ADH but not of those for PAH or UGT2B-rH4, while insulin deficiency induced premature expression of all four genes. We suggest that a set of genes whose expression is specifically induced in the liver upon birth can be prematurely induced by the hormones in utero.
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PMID:Identification of differentially expressed genes during hepatocytes development and characterization of their prenatal hormonal induction. 902 81


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