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)

Control rats or rats bearing Morris hepatoma 5123C (intact), 5123C (adrenalectomized), 7794A, 7800, 8999, 9121, or 9618A were fed a purified diet either deficient or adequate for vitamin B6. The concentration of pyridoxal phosphate in the plasma, host livers, and hepatomas was determined, as well as the in vitro rate of inactivation of induced tyrosine aminotransferase in homogenates of host livers and hepatomas. The results demonstrated the presence of a cysteine-independent inactivating system for tyrosine aminotransferase in hepatomas 5123C (adrenalectomized), 7800, 8999, and 9121. Only in hepatoma 9121 was there a dramatic influence of the dietary vitamin B6 on the rate of cysteine-independent inactivation. A cysteine-dependent inactivating system for the enzyme was present in all host livers and hepatomas. The rate of this in vitro inactivation for both host livers and hepatomas apparently was a function of the concentration of pyridoxal phosphate, but inactivation of tyrosine aminotransferase occurred at a significantly lower concentration of pyridoxal phosphate in the hepatomas than in the host livers.
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PMID:Effects of dietary vitamin B6 on the in vitro inactivation of rat tyrosine aminotransferase in host liver and Morris hepatomas. 3 80

Induction of tyrosine aminotransferase (TAT) (EC 2.6.1.5) by hydrocortisone was studied during cofactor (pyridoxal phosphate) depletion in hepatoma-bearing BUF strain female rats. Pairs of rats were matched for weight and age and one from each pair was fed ad libitum a diet lacking pyridoxine; the other (referred to as "pair-fed") was given the same diet supplemented with the vitamin, with the amount restricted to that consumed by the matched animal on the deficient diet. All animals were inoculated with Morris hepatoma no. 7777 cell after 21 days on the respective diets. TAT specific activity was determined weekly in host liver and hepatoma, in the presence and absence of cofactor, before and after the administration of hydrocortisone. Free and bound pyridoxal phosphate was estimated enzymatically. The average weight of hepatomas from pair-fed animals was 1.5-fold to twofold greater than that of hepatomas from animals on deficient diets. TAT activity of hepatomas was two times greater than that of host liver, and lack of dietary pyridoxine was without effect. Hormonal induction of enzymatic activity was maximal after the first week of tumor growth and subsequently reached minimal values. In pair-fed animals, tumor TAT was approximately 60% saturated with cofactor. In vitamin-deficient animals, only 6% of the tumor enzyme was saturated with the cofactor. The percent saturation of host liver TAT varied, with minimal values found in the vitamin-deficient animals. Hepatic and tumor pyridoxal phosphate content of pair-fed animals was unusually high (10 mug/g); in vitamin-deficient animals, only the coenzyme content of hepatomas was high (7.0 mug/g). The results showed that presence of the tumor altered the a) specific activity level of TAT and tissue content of cofactor, b) pattern of hormonal induction of the enzyme, and c) effects of the absence of dietary pyridoxine on TAT induction observed in animals without tumors.
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PMID:Hormonal induction of tyrosine aminotransferase activity in host liver and hepatoma no. 7777 of normal and cofactor-depleted animals. 24 64

Gyrate atrophy (GA), a degenerative disease of the human chorioretina, is associated with a deficiency of ornithine aminotransferase (OAT) activity, hyperornithinemia, and ornithinuria. We have characterized a cDNA clone for OAT (HLOAT) that was isolated from a cDNA library constructed from mRNA prepared from Hep G2 cells, a human hepatoma cell line. We have used HLOAT and a nearly full length OAT cDNA clone isolated from a rat liver library (RLOAT) to examine in cultured fibroblasts from individuals with GA and control individuals, the expression of OAT mRNA and the gross structure of the OAT gene. Northern blot analyses of total cellular RNA indicated that 3 of 3 control cell lines and 5 of 6 GA cell lines are capable of expressing an OAT related mRNA of approximately 2100 bases, the size of OAT mRNA. To date, this is the only case of GA in which a complete lack of OAT mRNA has been observed. Southern blot analyses of DNA isolated from these cell lines indicated that the gross structure of the OAT gene is usually not detectably altered in individuals with GA. However, a unique pattern of restriction fragments was observed upon digestion with Eco RI or Hind III of DNA from the GA cell line that does not express OAT mRNA. These unique Eco RI and Hind III fragments arise from the OAT structural gene and will serve as useful molecular markers that allow this particular defective OAT allele to be identified. When the cellular DNAs were digested with Hinf I and examined with a probe that corresponds to at least a portion of the active site of the enzyme, i.e., the pyridoxal phosphate binding site, identical patterns of fragments were detected in all samples. Therefore, it appears unlikely that the loss of OAT activity associated with these GA cases, 4 of which are pyridoxal phosphate responders, is the result of insertions or deletions in this region of the OAT gene. This study indicates that the lack of OAT enzyme activity associated with GA is the result of a variety of different molecular defects within the OAT gene.
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PMID:The ornithine aminotransferase gene in gyrate atrophy of the retina: analysis of expression and gross structure of this gene in cultured fibroblasts. 280 28

Vitamin B6 metabolism has been investigated in several highly and well-differentiated Morris hepatomas. Comparisons have been made with two poorly differentiated Morris hepatomas, with host livers obtained from tumor-bearing animals, and with fetal, neonatal, and adult rat liver. The pyridoxal phosphate content and the activities of pyridoxine kinase and pyridoxine phosphate oxidase of all Morris hepatomas examined were significantly less than those in adult host or control livers and generally fell in the range determined for fetal and neonatal liver. A similar pattern was not evident for the activity of pyridoxine phosphate phosphatase. Relative to control and host livers, the activity in hepatomas of the pyridoxal phosphate (PLP)-dependent enzyme, ornithine decarboxylase, was generally elevated. Dexamethasone, at a dose which caused an elevation in the activity of PLP-dependent tumor tyrosine aminotransferase, had no effect on PLP metabolism. The data indicate that tumor progression in the Morris hepatoma spectrum in relation to vitamin b6 metabolism falls into an onco-developmental pattern characterized by a diminished amount of tissue PLP and a diminished capability to metabolize precursor vitamer forms to PLP.
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PMID:Vitamin B6 metabolism in liver and liver-derived tumors. 612 59

Erythrocyte transketolase (ETK), glutathione reductase (EGR) and glutamate pyruvate transaminase (EGPT) enzyme activities and coenzyme effects (in vitro coenzyme stimulation) were studied in 30 random, 10 primary hepatoma, and 3 pellagrins natives from Mozambique. Twenty-nine subjects of the random group exhibited ETK coenzyme effects below 20%. Urinary thiamine levels in this group were in normal or high ranges. The primary hepatoma group had 4 with ETK coenzyme effects above 30%, and 3 of the 4 had low level urinary thiamine excretions. Of the three pellagra patients in the study, none showed biochemical vitamin B1 deficiency. All primary hepatoma and 23 random natives had EGR coenzyme effects above 30%, but the daily urinary riboflavin excretions correlated with the coenzyme effect in only the random group. EGPT activities were spread over a wide range. The random group with high EGPT activity showed a correlation with low coenzyme effect, while the primary hepatoma group did not exhibit this correlation. After 4-day single-vitamin treatment, vitamin B1 increased total ETK and vitamin B2 increased total EGR (after in vitro coenzyme saturation). Vitamin B6 did not increase total EGPT. Vitamin B2 was less effective on total EGR in primary hepatoma than in random subjects.
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PMID:Effects of vitamins B1, B2, B6 and C on erythrocyte enzymes in South African Bantu. 629 84

The metabolic transformations of labeled pyridoxine by hepatoma cells were studied. Buffalo rats were fed ad libitum a commercially prepared pyridoxine sufficient diet for 20 days at which time they were inoculated intramuscularly with hepatoma 7777 cells in both hind leg muscles. After tumor development, 50 microCi [6-3H] pyridoxine. HCl or 5 microCi [4,5-14C] pyridoxine. HCl was injected intraperitoneally per rat. Groups of animals were subsequently sacrificed at defined time intervals up to 9 days. Vitamin B6 labeled tumor metabolites were acid extracted and separated on a muBondapak C18 column by ion pairing reverse phase high performance liquid chromatography. A novel vitamin metabolite contributing up to 28.5% of extractable radioactivity was found with retention time different than any of the known vitamin B6 compounds. Its pattern of synthesis in vivo from labeled pyridoxine was PN leads to PNP leads to PLP leads to PMP leads to X. Preliminary GC-mass spectral data suggested the unknown consisted of more than one species. This communication reports on the metabolism of vitamin B6 and the isolation, synthesis in vivo and possible significance of the novel metabolite to the economy of the tumor cells.
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PMID:Metabolic interconversions of pyridoxine by Morris hepatoma No. 7777 cells. Synthesis of a novel metabolite. 683 Jan 50

The cDNA for the rat cytosolic branched chain aminotransferase (BCATc) has been cloned. The BCATc cDNA encodes a polypeptide of 410 amino acids with a calculated molecular mass of 46.0 kDa. By Northern blot analysis, BCATc message of approximately 2.7 kilobases was readily detected in rat brain, but was absent from liver, a rat hepatoma cell line, kidney, and skeletal muscle. When expressed in COS-1 cells, the enzyme is immunologically indistinguishable from the native enzyme found in rat brain cytosol. Comparison of the rat BCATc sequence with available data bases identified the Escherichia coli (and Salmonella typhimurium) branched chain aminotransferase (BCAT) and revealed a Haemophilus influenzae BCAT, a yeast BCAT, which is hypothesized to be a mitochondrial form of the enzyme, and the murine BCATc (protein ECA39). Calculated molecular masses for the complete proteins are 33.9 kDa, 37.9 kDa, 42.9 kDa, and 43.6 kDa, respectively. The rat BCATc sequence was 84% identical with murine BCATc, 45% identical with yeast, 33% identical with H. influenzae, 27% identical with the E. coli and S. typhimurium BCAT, and 22% identical with the evolutionary related D-amino acid aminotransferase (D-AAT) (Tanizawa, K., Asano, S., Masu, Y., Kuramitsu, S., Kagamiyama, H., Tanaka, H., and Soda, K. (1989) J. Biol. Chem. 264, 2450-2454). Amino acid sequence alignment of BCATc with D-AAT suggests that the folding pattern of the overlapping mammalian BCATc sequence is similar to that of D-AAT and indicates that orientation of the pyridoxal phosphate cofactor in the active site of the eukaryotic BCAT is the same as in D-AAT. Thus, BCAT are the only eukaryotic aminotransferases to abstract and replace the proton on the re face of the pyridoxal phosphate cofactor. Finally, requirements for recognition of substrate L-amino acid and alpha-carboxylate binding are discussed.
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PMID:Cloning and expression of the mammalian cytosolic branched chain aminotransferase isoenzyme. 853 Apr 59

The effect of vitamin B6 on the growth of a human hepatoma cell line HepG2 in culture was studied. The growth of HepG2 cells and protein synthesis were almost completely inhibited in medium supplemented with 5 mM pyridoxine. Pyridoxal was as effective as pyridoxine, but pyridoxamine showed no inhibitory action. The growth inhibition of HepG2 cells by pyridoxine was accompanied by a marked inhibition of secretion of plasma proteins, particularly albumin. Northern blot analysis of albumin mRNA showed that pyridoxine caused a rapid decrease in the expression of albumin gene. The electron-microscopic examination of pyridoxine-treated HepG2 cells revealed a smoothing of nuclear membrane, a decrease in the number of nucleoli, and an appearance of aggregated heterochromatin structures. These morphological features are compatible with the depressed transcriptional activity in the pyridoxine-treated cells. The mechanism by which vitamin B6 exerts its inhibitory effect was discussed in terms of our recent finding that vitamin B6 modulates expression of albumin gene by inactivating tissue-specific DNA-binding proteins. Binding of pyridoxal phosphate with tissue-specific transcription factors may reduce the capacity of these factors to interact with the regulatory region of albumin gene, resulting in the inhibition of the gene expression.
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PMID:Vitamin B6 suppresses growth and expression of albumin gene in a human hepatoma cell line HepG2. 929 Jan 29

Effects of potential sulfane sulfur precursors (diallyl disulfide, cystamine, 2-mercaptoethanol disulfide, thiosulfate, immunothiole and pyridoxal phosphate jointly with cystine) on [3H]-thymidine incorporation in human hepatoma (HepG2) cells were studied. Of the tested compounds, diallyl disulfide, cystamine and 2-mercaptoethanol disulfide were found to cause significant inhibition of HepG2 cells proliferation. Moreover, pyridoxal phosphate jointly with cystine suppressed [3H]-thymidine incorporation, but the differences between that system and control cells were insignificant. In the case of thiosulfate, no significant difference was observed. The present study shows that diallyl disulfide, found in garlic, is effective in inhibiting [3H]-thymidine incorporation in human hepatoma HepG2 cell cultures. Similar antiproliferative effects on HepG2 cells are shown by such systems being a source of sulfane sulfur as cystamine or 2-mercaptoethanol disulfide. Thus, it may be concluded that these donors of reactive sulfane sulfur may be responsible for inhibition of the proliferation of HepG2 cells. It is suggested that the observed antiproliferative properties of the investigated compounds are connected with the presence of the highly reactive sulfane sulfur.
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PMID:Effects of diallyl disulfide and other donors of sulfane sulfur on the proliferation of human hepatoma cell line (HepG2). 1171 84

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 oesophagus and of the liver. The increased risk attributable to alcohol consumption of 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 tumours, 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 is 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 tumour promoter. The metabolism of ethanol leads to the generation of acetaldehyde (AA) and free radicals. Evidence has accumulated that acetaldehyde is predominantly responsible for alcohol associated carcinogenesis. Acetaldehyde is carcinogenic and mutagenic, binds to DNA and proteins, destructs folate and results in secondary hyperproliferation. Acetaldehyde is produced by tissue alcohol hydrogenases, cytochrome P 4502E1 and through bacterial oxidative metabolism in the upper and lower gastrointestinal tract. Its generation or its degradation is modulated due to functional polymorphisms of the genes coding for the enzymes. Acetaldehyde can also be produced by oral and faecal bacteria. Smoking, which changes the oral bacterial flora, and poor oral hygiene also increase acetaldehyde. In addition, cigarette smoking and some alcoholic beverages such as calvados contain acetaldehyde. Other mechanisms by which alcohol stimulates carcinogenesis include the induction of cytochrome P-4502E1, which is associated with an enhanced production of free radicals and 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 behaviour such as cell cycle duration leading to hyperproliferation; nutritional deficiencies, such as methyl-, vitamin E-, folate-, pyridoxal phosphate-, zinc- and selenium deficiencies and alterations of the immune system eventually resulting in an increased susceptibility to certain virus infections such as hepatitis B virus and hepatitis C virus. In addition, local mechanisms may be of particular importance. Such mechanisms lead to tissue injury such as cirrhosis of the liver, a major prerequisite for hepatocellular carcinoma. Also, an alcohol-mediated increase in oestradiols may be at least in part responsible for breast cancer risk. Thus, all these mechanisms functioning in concert actively modulate carcinogenesis leading to its stimulation.
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PMID:Alcohol and cancer. 1508 51


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