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)

The risk of aflatoxin-induced hepatocarcinoma is greater in males than in females and is similarly higher in animals fed 20% casein diets than in those fed 5%. In this study, groups of male and female F344 rats were fed either a 5 or 20% casein diet for 6 weeks. Two hr after a 1-mg/kg i.p. dose of [3H]aflatoxin B1, animals were killed and four protein fractions were sequentially extracted from the liver chromatin of each. Within each treatment group, aflatoxin binding to nonhistones was greater than to histones, both before and after dialysis. Comparing treatments, the higher-risk factors were associated with a greater liver content of aflatoxin as well as with increased binding of both nondialyzable and dialyzable aflatoxin to the various fractions. The high degree of correlation between total liver content and adduct formation implicates the former as a major determinant of the latter. Also associated with the higher-risk factors was a shift in the distribution of dialyzable aflatoxin toward greater adduct formation with one of the nonhistone fractions, suggesting the possibility of a role for noncovalent aflatoxin:protein adducts in hepatocarcinogenesis.
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PMID:Effects of sex difference and dietary protein level on the binding of aflatoxin B1 to rat liver chromatin proteins in vivo. 681 51

Groups of male weanling rats bearing the transplantable Novikoff ascites hepatoma were fed diets containing graded levels of protein. The food intakes and weight gains were recorded daily. Seven days after inoculation of the rats with the tumor (6 days in Experiment 2), the rats were sacrificed, their organs were weighed, and the tumor and ascites fluid volumes were determined. These results were analyzed by the four-parameter mathematical model for physiological responses. It was found that tumor-bearing rats eat and gain weight at the same rates as control rats fed identical diets, implying that this rapidly growing tumor does not interfere with the normal food intake and growth control mechanisms and that food intakes and weight gains are predictable by the four-parameter model. Organ growth was regulated in both normal and tumor-bearing rats but some actual organ weights in tumor-bearing rats were smaller than in control rats due to the presence of the tumor. However, other organs (spleen, lung, kidneys, and small intestine) of the tumor-bearing rats showed significant differences (p less than 0.01, Student's t test) from control rats. It was also possible to predict the growth of the tumor on the basis of the casein content of the diet.
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PMID:Prediction of food intakes, weight gains, organ weights, and tumor size in tumor-bearing rats by the four-parameter mathematical model for physiological responses. 724 59

A cyclic-nucleotide independent heparin-sensitive nuclear protein kinase (NII) from the Morris hepatoma 3924A has been purified by a combination of ion exchange and affinity chromatographic procedures and velocity gradient centrifugation. The purified kinase had a molecular weight of 140,000 as determined by gel filtration. Two polypeptides (Mr = 42,000 and 25,600) were present in the purified preparation in approximately equimolar concentrations. The protein kinase employed Mg2+ and Co2+ as divalent ion and preferred the nonhistone proteins, casein or phosvitin, as protein acceptors. In the presence of Mg2+, it utilized both ATP and GTP as substrates and transferred the terminal nucleotide phosphate to serine and threonine residues of the protein acceptor. Phosphorylation of casein was stimulated by polyamines, particularly spermine. This polyamine preferentially enhanced phosphate transfer to threonine. The enzyme was inhibited by several compounds including heparin, the o-n-octyloxime of rifamycin (AF/013), 3'-dATP, o-phenanthroline, polynucleotides, and ADP. Of these inhibitors, heparin was the most potent and completely abolished kinase activity at a concentration of 0.1 micrograms/ml. The kinase could be autophosphorylated by incubation with Mg2+ and [gamma-32P]ATP; under these conditions phosphorylation was confined to the polypeptide of Mr = 24,600 and was completely inhibited by heparin. Based on the unique properties of NII protein kinase (ability to use GTP, stimulation by spermine, sensitivity to heparin), a selective assay was developed which could measure NII activity in the presence of other nuclear kinases. Under the optimal assay conditions, the nuclear extract of hepatoma 3924A was found to contain at least five times more NII kinase activity than that of normal adult liver. Analysis of extensively purified preparations from the two sources confirmed these results. After purification 11 times more NII protein kinase activity was obtained from hepatoma 3924A than from liver. Although hepatoma and liver protein kinases exhibited many common properties, they displayed distinct nucleotide saturation kinetics. The apparent Km for ATP was 10 microM for hepatoma protein kinase and 24 microM for the liver enzyme.
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PMID:A heparin-sensitive nuclear protein kinase. Purification, properties, and increased activity in rat hepatoma relative to liver. 725 4

The phosphorylation of endogenous membrane proteins by an endogenous protein kinase was studied in isolated plasma membranes from AH-66 hepatoma ascites cells using [gamma-32P]ATP as a precursor. The phosphorylation occurred very rapidly in the presence of 10 mM Mg2+ and reached a maximal level at 2 min. Ca2+ strongly inhibited the phosphorylation reaction and antagonized the activation produced by Mg2+. Neither cyclic AMP nor cyclic GMP had a significant effect on the phosphorylation. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis and autoradiography showed that only membrane proteins ranging in molecular weight from 125,000 to 200,000 were heavily phosphorylated and those of less than 60,000 molecular weight were not phosphorylated at all. The protein kinase activity was readily extractable from the plasma membranes with 1 mM EDTA at pH 8.5. Among exogenous substrates, the extracted protein kinase catalyzed the phosphorylation of histone, protamine and phosvitin rather than casein. When the extracted protein kinase was subjected to chromatography on DEAE-Sepharose, a single major peak of cyclic AMP-independent protein kinase was eluted at a position quite different from those of the cytosolic protein kinases.
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PMID:Endogenous protein phosphorylation in isolated plasma membranes of AH-66 hepatoma ascites cells. 728 78

A nuclear protein kinase, designated NII, was purified essentially to homogeneity from the Morris hepatoma 3924A. In the presence of excess Mg2+, phosphorylation of casein by the kinase was stimulated by spermine (1-5 mM) and was inhibited completely by 0.1 microgram/ml heparin. The apparent Km for casein was reduced in the presence of spermine. Spermine preferentially augmented phosphorylation of threonine residues. The kinase was also associated with highly purified RNA polymerase I and appears to correspond to two polypeptides (Mr 42,000 and 24,600) of the polymerase. RNA polymerase I polypeptides of Mr 120,000 (S2), Mr 65,000 (S3) and Mr 24,600 (S5) were phosphorylated by the endogenous kinase. Spermine enhanced phosphorylation of the RNA polymerase I subunits as much as 20-fold. Phosphorylation activated RNA polymerase I; the phosphorylated enzyme synthesized longer product with no apparent effect on the number of RNA chains initiated.
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PMID:Spermine-mediated phosphorylation of RNA polymerase I and its effect on transcription. 733 1

Aflatoxicol (AFL), a major metabolite of aflatoxin B1 (AFB1) in the Mt. Shasta rainbow trout (Salmo gairdneri), was found to produce hepatocellular carcinoma in trout. It was administered in a casein diet to duplicate groups of 120 fingering trout. In the same manner, additional duplicate groups received one of the following: no toxicant; AFB1; the diastereomer of AFL (AFL'); cyclopropenoid fatty acids (CPFA); and CPFA plus AFB1, AFL, and AFL'. Eight months after the initiation of the study, the following incidences of carcinoma were observed: control (0%); 20 ppb AFB1 (56%); 29 ppb AFL (26%); 61 ppb AFL' (0%); 50 ppm CPFA (3%); 20 ppb AFB1 plus 50 ppm CPFA (96%); 29 ppb AFL plus 50 ppm CPFA (94%); and 61 ppb AFL' plus 50 ppm CPFA (55%), showing both the carcinogenicity of AFL and the synergistic effects of CPFA. Twelve-month incidences were correspondingly higher in all cases. Aflatoxin M1, another metabolite of AFB1 in rainbow trout, was reported previously to be carcinogenic in trout. These results support the hypothesis that metabolism in rainbow trout does not effectively detoxify AFB1, but rather the formation of AFL extends the carcinogenicity of AFB1 and may contribute to the high sensitivity of rainbow trout to AFB.
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PMID:Aflatoxicol-induced hepatocellular carcinoma in rainbow trout (Salmo gairdneri) and the synergistic effects of cyclopropenoid fatty acids. 745 48

There is evidence that the development of hepatocarcinoma in rats fed a methyl-deficient diet is associated with oxidative stress. We investigated, therefore, whether the tissue concentrations of the antioxidant vitamins ascorbic acid (AA) and alpha- and gamma-tocopherol (T) are altered in methyl/folate deficiency. We also measured retinol concentrations in tissues and hepatic mRNA expression of heme oxygenase (HO1). A 6% gelatin, 6% casein diet, devoid of choline and folate (CFD) was selected based on the high rate of tumor development in rats fed this diet. Spectrophotometric measurement of AA and HPLC determination of tissue T and retinol showed decreased concentrations of AA in blood; alpha- and gamma-T in lung, heart and plasma, alpha-T and retinol in liver; retinol in lung; and increased expression of hepatic HO1 mRNA. Similar alterations in tissue vitamin concentrations were found when the CFD diet devoid of niacin (CFND) was fed. Reducing alpha-T in the CFND diet (CFNED) further decreased hepatic alpha-T concentrations. These results show that chronic methyl/folate deficiency is associated with a compromised antioxidant defense system.
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PMID:Vitamins C, E and A and heme oxygenase in rats fed methyl/folate-deficient diets. 937 73

Hepatitis C virus (HCV) has a positive-strand RNA genome that codes for a polyprotein precursor, which is processed co- and post-translationally by cellular and viral proteinases into three structural and at least six non-structural (NS) proteins. The NS5A protein, expressed in mammalian cells, exists in two phosphorylated forms of 56-kDa and 58-kDa. In this study, we provide evidence for a stable association between NS5A and a protein kinase from HeLa cells and hepatocellular carcinoma (HepG2) cells by co-immunoprecipitation and by affinity to immobilized glutathione-S-transferase (GST)-NS5A fusion protein produced in E. coli. This protein kinase could phosphorylate in vitro the native NS5A on serine residues, (GST)-NS5A, histone H1, and casein as substrates. In addition, the GST-NS5A was also phosphorylated in vitro by the cAMP-dependent protein kinase A-alpha catalytic subunit.
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PMID:Hepatitis C virus NS5A protein is phosphorylated in vitro by a stably bound protein kinase from HeLa cells and by cAMP-dependent protein kinase A-alpha catalytic subunit. 940 82

Persistent infection with hepatitis B virus (HBV) is one of the primary risk factors for human hepatocellular carcinoma (HCC). In a human ecological study, we have shown that, in addition to HBV, animal food consumption also significantly contributes to the variance of HCC. To test the interacting effect of HBV and animal food consumption on the development of HCC, we investigated HBV expression in HBV transgenic mice fed three levels of casein diet. HBV expression in transgenic animals was substantially inhibited when dietary casein was reduced from the traditional level of 22% to the level of 6%. Northern analysis revealed that suppression of HBV was derived from both the upstream albumin promoter and the internal HBV promoter. Immunochemical staining of liver sections indicated that only a few hepatocytes around the central vein expressed viral surface antigen (HBsAg) in the 6% casein animals, whereas virtually all hepatocytes stained positively for HBsAg in the 22% dietary casein animals. Serum HBsAg concentrations at 4 months were increased by 1.6-, 2.1-, and 5.1- fold over baseline for animals fed the 6%, 14%, and 22% casein diets, respectively. Correspondingly, liver injury was much less severe in animals fed 6% casein diet than in those fed 14% and 22% casein diets. These results demonstrate that a low casein diet is a potent suppresser of HBV transgene and HBV-induced liver injury, suggesting that diet management may be a practical means to aid in the control HBV infection.
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PMID:Repression of hepatitis B virus (HBV) transgene and HBV-induced liver injury by low protein diet. 941 70

Estrogenic isoflavones, such as genistein and daidzein, are present in virtually all natural-ingredient rodent diets that use soy as a source of protein. Since these compounds are endocrine-active, it is important to determine whether the amounts present in rodent diets are sufficient to affect sexual development. The present study consisted of in vitro and in vivo parts. In the in vitro portion, human hepatoma cells were transfected with either rat estrogen receptor (ER) alpha or beta plus an estrogen-responsive luciferase reporter gene. Genistein and daidzein were complete agonists at both ERs, genistein being more potent than daidzein, and both compounds were more potent at ER beta than ER alpha. In combined studies with estradiol, genistein exerted additive effects with estradiol in vitro. In the in vivo portion of the study, groups of six pregnant Sprague-Dawley females were fed one of the following four diets, and the pups were maintained on the same diets until puberty: (1) a natural-ingredient, open-formula rodent diet (NIH-07) containing 16 mg genistein and 14 mg daidzein per 100 g of feed; (2) a soy- and alfalfa-free diet (SAFD) in which casein and corn oil were substituted for soy and alfalfa meal and soy oil, respectively, that contained no detectable isoflavones; (3) SAFD containing 0.02% genistein (GE.02); or (4) SAFD containing 0.1% genistein (GE.1). In the GE.1 group, effects of dietary genistein included a decreased rate of body-weight gain, a markedly increased (2.3-fold) uterine/body weight (U/BW) ratio on postnatal day (pnd) 21, a significant acceleration of puberty among females, and a marginal decrease in the ventral prostate weight on postnatal day (pnd) 56. However, developmental differences among the groups fed SAFD, GE.02, or NIH-07 were small and suggested minimal effects of phytoestrogens at normal dietary levels. In particular, on pnd 21, the U/BW ratio of the GE.02 and NIH-07 groups did not differ significantly from that of the SAFD group. Only one statistically significant difference was detected between groups fed SAFD and NIH-07: the anogenital distance (AGD) of female neonates on pnd 1 whose dams were fed NIH-07 was 12% larger than that of neonates whose dams were fed SAFD. The results suggest that normal amounts of phytoestrogens in natural-ingredient rodent diets may affect one developmental parameter, the female AGD, and that higher doses can affect several other parameters in both males and females. Based on these findings, we do not suggest replacing soy- and alfalfa-based rodent diets with phytoestrogen-free diets in most developmental toxicology studies. However, phytoestrogen-free diets are recommended for endocrine toxicology studies at low doses, to determine whether interactive effects may occur between dietary phytoestrogens and man-made chemicals.
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PMID:Developmental effects of dietary phytoestrogens in Sprague-Dawley rats and interactions of genistein and daidzein with rat estrogen receptors alpha and beta in vitro. 1054 25


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