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)

Treatment of rat hepatoma dRLh-84 cells with sodium arsenite, cadmium chloride and cobalt chloride resulted in marked induction of protein with a molecular mass of 32 kDa. To examine the possibility that the induced 32 kDa protein may be heme oxygenase, the enzyme activity was measured, and then the activity in the cells increased by these metals, and heat shock treatments. Immunoblot analysis showed that the induction of 32 kDa protein reacted with anti-heme oxygenase antibody occurred by the treatments. Northern blot analysis confirmed that the induction of heme oxygenase by arsenite, cadmium and cobalt, and by hyperthermia was regulated at transcriptional level. These findings support the hypothesis that the 32 kDa stress protein induced by heavy metals in rat hepatoma cells is heme oxygenase.
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PMID:Induction of heme oxygenase in rat hepatoma cells by exposure to heavy metals and hyperthermia. 324 Mar 16

Sn-protoporphyrin IX (SnPP), an inhibitor of heme oxygenase and a potential therapeutic agent for neonatal hyperbilirubinemia, is bound tightly by hemopexin. The apparent dissociation constant (Kd) at pH 7.4 is 0.25 +/- 0.15 microM, but estimation of the Kd for the SnPP-hemopexin complex is hampered by the fact that at physiological pH SnPP exists as monomers and dimers, both of which are bound by hemopexin. SnPP is readily displaced from hemopexin by heme (Kd less than 1 pM). The hemopexin-SnPP interaction, like that of heme-hemopexin, is dependent on the histidine residues of hemopexin. However, as expected from the differences in the coordination chemistries of tin and iron, the stability of the histidyl-metalloporphyrin complex is lower for SnPP-hemopexin than for mesoheme-hemopexin. Nevertheless, when SnPP binds to hemopexin, certain of the ligand-induced changes in the conformation of hemopexin which increase the affinity of the protein for its receptor are produced. Binding of SnPP produces the conformational change in hemopexin which protects the hinge region of hemopexin from proteolysis, but SnPP does not produce the characteristic increase in the ellipticity of hemopexin at 231 nm that heme does. Competition experiments confirmed that human serum albumin (apparent Kd = 4 +/- 2 microM) has a significantly lower affinity for SnPP than does hemopexin. Appreciable amounts of SnPP (up to 35% in adults and 20% in neonates) would be bound by hemopexin in the circulation, and the remainder of SnPP would be associated with albumin due to the latter's high concentration in serum. Essentially no non-protein-bound SnPP is present. Importantly, SnPP-hemopexin binds to the hemopexin receptor on mouse hepatoma cells with an affinity comparable to that of heme-hemopexin and treatment of the hepatoma cells with SnPP-hemopexin causes a rapid increase in the steady state level of heme oxygenase messenger RNA. These results show that hemopexin participates in the transport of SnPP to heme oxygenase and in its regulation by SnPP.
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PMID:Interaction of hemopexin with Sn-protoporphyrin IX, an inhibitor of heme oxygenase. Role for hemopexin in hepatic uptake of Sn-protoporphyrin IX and induction of mRNA for heme oxygenase. 337 22

Synthesis of metallothionein-I (MT-I) and heme oxygenase mRNAs is rapidly and transiently induced by H2O2 in mouse hepatoma cells (Hepa) and this effect is blocked by catalase. Menadione, which generates free radicals, also induces these mRNAs. Deletion mutagenesis revealed that a region between -42 and -153 in the mouse MT-I promoter was essential for induction of a CAT reporter gene. A multimer of a 16 bp sequence (-101 to -86) that includes an antioxidant response element and overlapping adenovirus major late transcription factor binding site elevated basal expression and allowed induction by H2O2 when inserted upstream of a minimal promoter. However, deletion of this region (-100 to -89) from the intact MT-I promoter (-153) did not completely eliminate response. Multiple copies of a metal response element also permitted response to H2O2. These results suggest that induction of MT-I gene transcription by H2O2 is mediated by at least two different elements within the proximal MT-I gene promoter and suggest a previously undescribed function of the MRE. Induction of MT gene transcription by ROS and the subsequent scavenging of ROS by the MT peptide is reminiscent of the metal regulatory loop and is consistent with the hypothesized protective functions of MT.
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PMID:Transcriptional induction of the mouse metallothionein-I gene in hydrogen peroxide-treated Hepa cells involves a composite major late transcription factor/antioxidant response element and metal response promoter elements. 780 Apr 94

The effects of interleukin-6 (IL-6), the major inducer of the acute-phase reaction, on the expression of cytochrome P450IA1 (CYPIA1) were examined using human HepG2 hepatoma cells. Treatment of cells with IL-6 decreased the level of 3-methylcholanthrene-induced CYPIA1 protein and its mRNA. Nuclear runoff analysis revealed that the effect of IL-6 was largely transcriptional. IL-6 treatment of HepG2 cells increased mRNA for microsomal heme oxygenase, the rate-limiting enzyme in heme catabolism, suggesting that the suppressive effect of IL-6 on CYPIA1 mRNA may be due to a loss of heme. Consistent with this hypothesis, simultaneous treatment of cells with Sn-mesoporphyrin, an inhibitor of heme oxygenase, prevented the IL-6-mediated suppression of CYPIA1. These findings suggest that the suppression of P450IA1 mRNA by IL-6 appears to occur, at least in part, from the decline in free heme content as a result of the induction of heme oxygenase. Our results raise the possibility that other physiological as well as environmental stimuli which affect cellular heme concentrations may also modulate the expression of P450s.
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PMID:Suppression of cytochrome P450IA1 by interleukin-6 in human HepG2 hepatoma cells. 816 48

The role of inorganic metals and metalloporphyrins in the induction of mRNAs for haem oxygenase and heat-shock protein 70 (hsp70), the two heat-shock proteins, was examined in human HepG2 and Hep3B hepatoma cells. SnCl2, but not Sn-protoporphyrin, was found to be a potent inducer of both haem oxygenase and hsp70 mRNAs. In contrast, CoCl2, ZnCl2 and FeCl2 caused little induction of haem oxygenase and hsp70 mRNAs, whereas the porphyrin complexes of these metals strongly induced haem oxygenase mRNA, without influencing the level of hsp70 mRNA. The induction process was largely transcriptional, as judged by the inhibition of induction by actinomycin D, but not by cycloheximide, and by increased transcription demonstrated by nuclear run-off analysis. Since CoCl2 is a potent inducer of haem oxygenase in vivo in animals, the possibility of the biosynthesis of Co-protoporphyrin was examined in human hepatoma cells by incubating them with CoCl2 and protoporphyrin, or delta-aminolaevulinate (ALA), the precursor of protoporphyrin. Both types of treatment led to a potent induction of haem oxygenase mRNA. Co-protoporphyrin formation was also spectrally demonstrated in cells incubated with the metal and ALA. The results of this study indicate that certain metals, e.g. SnCl2, may directly induce haem oxygenase mRNA, whereas with other elements, incorporation of the metal into the porphyrin macrocycle is necessary for induction. Therefore CoCl2, like haemin, may activate the haem oxygenase gene via a haem-responsive transcription factor, whereas SnCl2 may exert its effect via a metal-responsive transcription factor.
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PMID:The role of inorganic metals and metalloporphyrins in the induction of haem oxygenase and heat-shock protein 70 in human hepatoma cells. 838 46

Effect of recombinant human interleukin-11 (rhIL-11) on the expression of transcripts encoding microsomal heme oxygenase (HO), the rate-limiting enzyme in heme catabolism, and haptoglobin (Hpt), a major acute-phase protein, were examined in human HepG2 hepatoma cells. Treatment of HepG2 cells with rhIL-11 elicited an increase in HO mRNA in a dose- and a time-dependent fashion. The dose response curve, its magnitude of response and its time course were similar to those observed with recombinant human interleukin-6 (rhIL-6). In contrast, rhIL-11 had a far smaller effect on the level of Hpt mRNA than did rhIL-6. These findings demonstrate that the two cytokines are similar in regulating heme catabolism, while markedly different in inducing certain acute-phase proteins.
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PMID:Effect of interleukin-11 on the levels of mRNAs encoding heme oxygenase and haptoglobin in human HepG2 hepatoma cells. 850 20

Heme oxygenase catalyzes the degradation of heme into biliverdin, carbon monoxide, and iron. Two forms of this enzyme, heme oxygenase-1 and -2, have been identified; only heme oxygenase-1 is subject to induction by heme, metal ions, and other chemical and physical perturbations (e.g. drugs, oxidants, and heat shock). Primary chick embryo liver cells are widely used for the study of heme metabolism because of their ease of preparation, low cost, and high degree of similarity to human heme metabolism. Nonetheless, this system has some limitations: new cultures must be prepared every week; the resulting cell populations are non-homogeneous; and cells are short-lived, limiting the feasible duration of time course and transfection studies. LMH cells are the first chicken hepatoma cell line to be established. The aim of this study was to characterize the regulation of heme oxygenase-1 in LMH cells, and to compare this regulation to that previously described in primary chick embryo liver cells. The induction of heme oxygenase-1 was assessed by measuring changes in mRNA levels or enzyme activities in response to several treatments, including heme, heavy metals, sodium arsenite, and heat shock, which have been shown to increase the expression of heme oxygenase. Similarities were observed with respect to regulation of heme oxygenase-1 expression in primary hepatocytes and LMH cells. We report the first measurable heat shock response of heme oxygenase-1 in CELC or LMH cells; and show that LMH cells are a useful model for the study of heme oxygenase-1 regulation.
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PMID:Induction of heme oxygenase-1 in LMH cells. Comparison of LMH cells to primary cultures of chick embryo liver cells. 864

The expression of hsp70-the inducible member of the corresponding heat shock gene family-of the oxidative stress marker gene heme oxygenase (HOx), and of the immediate early response genes c-fos and c-jun has been studied in FAO hepatocarcinoma cells depleted of polyamines and exposed to heat shock. Depletion of polyamines was obtained in short-term experiments (24-48 hours) by the use of alpha difluoromethylornithine (DFMO), a classical inhibitor of ornithine decarboxylase (ODC), or of the combination of the newly available inhibitors of ODC and S-adenosylmethionine decarboxylase, i.e., (2R,5R)-hept-6-yne-2,5-diamine (MAP) and 5'{[(Z)-4-aminobut-2-enyl]methylanino}-5-deoxyadeno-si ne (AbeAdo). Under our experimental conditions polyamine imbalance was realized without appreciable growth-related genes. Decreases of putrescine and spermidine 48 hours after DFMO prevented the induction of hsp70 messenger RNA (mRNA), whereas depletion spermidine and spermine obtained with MAP/AbeAdo decreased intensity and duration of post-heat shock accumulation of hsp70 mRNA. Inductions of HOx, c-jun and c-fos were also inhibited. Because MAP/AbeAdo caused also an intracelluar accumulation of putrescine, we tested the effect of exogenous putrescine, which was found to stabilize the mRNAs for hsp70 and c-jun. Hsp70 and HOx are thought to play a protective role, and the proteins of c-jun and c-fos constitute the transcription factor activator protein-1, which is involved in the transcription of many defensive products. Therefore, the integrity of polyamine pool seems to be a necessary permissive condition for an effective response of the cells to adverse environmental changes.
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PMID:Effects of polyamine imbalance on the induction of stress genes in hepatocarcinoma cells exposed to heat shock. 870 55

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

Hemopexin (Hx) binds heme with a very high affinity (Kd<0.1 pmol/L). It has been implicated as a major vehicle for the transport of heme into liver cells, involving a receptor-mediated recycling mechanism. However, previous studies indicated that heme is not taken up by cultured embryonic chick or adult rat hepatocytes by such a mechanism, because heme added as heme hemopexin failed to affect heme-responsive activities of 5-aminolevulinic acid synthase and heme oxygenase. Here, we investigated the importance of hemopexin in hepatic heme uptake in cultured rat hepatocytes and human HepG2 hepatoma cells, and determined the number and species specificity of hemopexin receptors on the rat hepatocytes. We also tested whether there is a difference between heterologous and homologous hemopexins. We found the following: 1) heme is inhibited from associating with hepatocytes by apo hemopexins from rat, human, rabbit, and chicken; 2) heme readily associates with hepatocytes when heme hemopexin preparations are added in which the ratio of heme to hemopexin exceeds 1.0; 3) heme induces heme oxygenase mRNA in rat hepatocytes and this induction is prevented by excess hemopexin; and 4) rat hepatocytes exhibit only about 2,000 hemopexin receptors per cell when using rat hemopexin, and none when using hemopexin of rabbit and human. We conclude that hemopexin plays a limited role in heme uptake by cultured hepatocytes and hepatoma cells, and that heme which exceeds the hemopexin binding capacity is taken up directly from heme-albumin.
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PMID:Hemopexin from four species inhibits the association of heme with cultured hepatoma cells or primary rat hepatocytes exhibiting a small number of species specific hemopexin receptors. 950 Jul 11


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