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)

A recent study from our laboratory demonstrated that cyclosporine (CsA), a prototype immunosuppressant, enhanced the growth of carcinogen-induced enzyme altered foci in rat liver, suggesting that CsA may stimulate development of hepatocellular carcinomas. In the present study, we examined (i) whether CsA accelerates development of hepatocellular carcinomas in experimental animals, (ii) whether CsA stimulates the proliferation of resting hepatocyte in vivo and (iii) whether CsA modulates the production of growth factors implicated in liver cell growth, hepatocyte growth factor (HGF), transforming growth factor alpha (TGF alpha) and transforming growth factor beta 1 (TGF beta 1). Foci of hepatocytes, positive for glutathione S-transferase placental form were induced in male F344 rats by a single dose of diethylnitrosamine followed by 7 weeks promotion by a choline-deficient diet. The animals were then divided in two groups, and subsequent development of hepatocellular carcinomas was compared in rats fed a basal diet or a basal diet containing 0.015% CsA. Development of hepatocellular carcinoma was accelerated in the rats maintained on a CsA diet. Feeding a CsA diet as the sole treatment, for 2, 4 and 10 weeks induced significant increases in liver weight, and resulted also in an enhanced incorporation by hepatocytes of 5-bromo-2-deoxy-uridine. Serum levels of glutamate-oxaloacetate transferase, glutamate-pyruvate transferase and lactic dehydrogenase were not altered by feeding a CsA diet. Northern Blot analyses of the expression of HGF, TGF alpha and TGF beta 1 mRNAs in the liver showed similar patterns of expression between rats fed a basal diet and a CsA diet. The levels of HGF mRNA were not altered in the lungs and kidneys of rats fed a CsA diet. These results indicate that CsA stimulates rat liver cell proliferation in vivo without inducing liver cell necrosis, and that this effect may contribute to accelerated development of hepatocellular carcinomas in rats fed a CsA diet. As previously observed with BR 931, a hypolipidemic peroxisome proliferator, stimulation of liver cell growth by CsA did not entail changes in the production of HGF, TGF alpha or TGF beta 1.
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PMID:Cyclosporine stimulates hepatocyte proliferation and accelerates development of hepatocellular carcinomas in rats. 835 42

Exposure of rodents or their cells in culture to low doses of a wide variety of chemical agents, many of which are electrophiles, evokes a coordinated metabolic response that protects these systems against the toxicity (including mutagenicity and carcinogenicity) of higher doses of the same or other electrophiles. This response involves enhanced transcription of Phase 2 enzymes: glutathione transferases, NAD(P)H:quinone reductase, UDP-glucuronsyltransferases, and epoxide hydrolase, as well as the elevation of intracellular levels of reduced glutathione. We suggest that this cellular adaptation, which occurs in the liver and many peripheral tissues, be designated as the "Electrophile Counterattack" response. Seven families of highly diverse chemical agents that elicit this response include: oxidatively labile diphenols and quinones; Michael reaction acceptors (olefins conjugated to electron-withdrawing groups); isothiocyanates; organic hydroperoxides; vicinal dimercaptans; trivalent arsenicals; heavy metals (HgCl2, CdCl2) as well as mercury derivatives with high affinities for sulfhydryl groups; and 1,2-dithiole-3-thiones. An analysis of the molecular mechanisms of these enzyme inductions was carried out by transient expression in hepatoma cells of a plasmid containing a 41-bp enhancer element derived from the 5'-upstream region of the mouse glutathione transferase Ya gene, and the promoter region of this gene, linked to a human growth hormone reporter gene. The concentrations of 28 inducers (belonging to the seven chemical classes) required to double growth hormone production in this system spanned a range of four orders of magnitude and were closely and linearly correlated with the concentrations of the same compounds required to double the specific activity of quinone reductase in murine hepatoma cells. We therefore conclude that the regulation of these Phase 2 enzymes (and possibly also that of glutathione synthesis) by all of these inducers is mediated by the same enhancer element that contains AP-1-like sites. Similar enhancer sequences are present in the rat glutathione transferase Ya gene, and in the upstream regulatory regions of the quinone reductase genes of rat and human liver.
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PMID:The electrophile counterattack response: protection against neoplasia and toxicity. 835 13

Inductions of detoxication (phase 2) enzymes, such as glutathione transferases and NAD(P)H:(quinone-acceptor) oxidoreductase, are a major mechanism for protecting animals and their cells against the toxic and neoplastic effects of carcinogens. These inductions result from enhanced transcription, and they are evoked by diverse chemical agents: oxidizable diphenols and phenylenediamines; Michael reaction acceptors; organic isothiocyanates; other electrophiles--e.g., alkyl and aryl halides; metal ions--e.g., HgCl2 and CdCl2; trivalent arsenic derivatives; vicinal dimercaptans; organic hydroperoxides and hydrogen peroxide; and 1,2-dithiole-3-thiones. The molecular mechanisms of these inductions were analyzed with the help of a construct containing a 41-bp enhancer element derived from the 5' upstream region of the mouse liver glutathione transferase Ya subunit gene ligated to the 5' end of the isolated promoter region of this gene, and inserted into a plasmid containing a human growth hormone reporter gene. When this construct was transfected into Hep G2 human hepatoma cells, the concentrations of 28 compounds (from the above classes) required to double growth hormone production, and the concentrations required to double quinone reductase specific activities in Hepa 1c1c7 cells, spanned a range of four orders of magnitude but were closely linearly correlated. Six compounds tested were inactive in both systems. A 26-bp subregion of the above enhancer oligonucleotide (containing the two tandem "AP-1-like" sites but lacking the preceding ETS protein binding sequence) was considerably less responsive to the same inducers. We conclude that the 41-bp enhancer element mediates most, if not all, of the phase 2 enzyme inducer activity of all of these widely different classes of compounds.
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PMID:Chemical and molecular regulation of enzymes that detoxify carcinogens. 838 53

Acute hepatitis spontaneously develops in the Long-Evans Cinnamon rat at the age of 4 mo, and eventually hepatocellular carcinoma develops after the chronic hepatitis that persists for over a year. Previously, abnormal copper accumulation was found in the livers of Long-Evans Cinnamon rats from birth, and it was reported that short-term administration of D-penicillamine, a copper-chelating agent, prevented acute hepatitis in Long-Evans Cinnamon rats. In this study we investigated whether long-term administration of D-penicillamine could also prevent chronic hepatitis and subsequent hepatocellular carcinoma in Long-Evans Cinnamon rats. During long-term observation, which was continued from 11 to 70 wk after birth, no elevation of serum transaminase levels was observed in the Long-Evans Cinnamon rats treated with D-penicillamine. Moreover, no histological changes characteristic of the chronic hepatitis were observed in D-penicillamine-treated Long-Evans Cinnamon rats, which were killed at 70 wk of age. Furthermore, placental glutathione S-transferase-positive foci, described as a marker for preneoplastic lesions in the liver, were not detected, and thus hepatocarcinogenesis was completely prevented in D-penicillamine-treated Long-Evans Cinnamon rats. We also found that the amount of 8-hydroxy-deoxyguanosine, one of oxidative DNA damage products in the liver, was decreased in the Long-Evans Cinnamon rats treated with D-penicillamine. These findings suggest that a process of the prolonged liver-cell injury and regeneration was essential for spontaneous development of hepatocellular carcinoma in Long-Evans Cinnamon rats with abnormal copper metabolism.
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PMID:Prevention of spontaneous hepatocellular carcinoma in Long-Evans cinnamon rats with hereditary hepatitis by the administration of D-penicillamine. 839 59

The hepatoproliferative effects of 2 antiestrogens, tamoxifen and toremifene, were compared in a sequential 15-month study in which 2 doses of each compound were administered by daily gavage to female Sprague-Dawley rats for up to 12 months. The doses were 11.3 and 22.6 mg/kg for tamoxifen and 12 and 24 mg/kg for toremifene. There were scheduled sacrifices at 3, 6, 12, and 15 months, the latter including a 3-month recovery period from the 12th through the 14th month. In the chronic toxicity study, tamoxifen at 22.6 mg/kg produced 100% incidence of hepatocellular carcinoma at the 12- and 15-month sacrifice intervals and 67% and 71% incidences at the 11.3-mg/kg dose. Sequential observations showed an increased incidence of glutathione S-transferase-positive foci of hepatocellular alteration by 3 months with tamoxifen in the absence of hepatotoxicity, with the first liver carcinoma appearing by 6 months of treatment. Unscheduled deaths occurring beyond 7.5 months in the tamoxifen treated groups were due in almost all cases to liver cancer. In striking contrast, toremifene did not produce any hepatoproliferative effects at 12- and 24-mg/kg dose levels, nor in a pilot study at 48 mg/kg. The 24-mg/kg dose of toremifene exerted an inhibiting effect on foci of hepatocellular alteration in rat liver detectable by glutathione S-transferase immunohistochemistry at 3 months and by conventional histology at 12 months. An antiproliferative effect was also evident in mammary gland and anterior pituitary where both toremifene and tamoxifen suppressed tumor incidence in comparison to the control group. The ability of these drugs to modify rat liver DNA after p.o. administration was investigated using the 32P-postlabeling assay. Administration of tamoxifen at 45 mg/kg for 7 days produced liver DNA nucleoside modifications represented by 7 spots on the autoradiogram. Unlike tamoxifen, toremifene did not produce any modified bases in rat liver DNA detectable by the 32P-postlabeling technique. The dose levels of tamoxifen that are strongly hepatocarcinogenic in the rat are compared with doses used in humans in various applications. Taking internal drug exposure into account, we conclude that the margin of safety for use of tamoxifen as an endocrine prophylactic agent for healthy, but breast cancer prone, women is questionable.
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PMID:Major difference in the hepatocarcinogenicity and DNA adduct forming ability between toremifene and tamoxifen in female Crl:CD(BR) rats. 840 24

A high incidence of hepatocellular carcinoma (HCC) was observed in mice fed a choline-deficient diet containing 0.1% ethionine (CDE) for 19 months. HCC was present in 85% of CDE mice and in 22% of choline-deficient (CD) mice not receiving ethionine. This strong hepatocarcinogenicity of the CDE diet was concomitant with a severe decrease in plasma and liver alpha-tocopherol (Toc) to 60 and 35%, respectively, of those contained in choline-supplemented (CS) control mice. We previously found that this dietary-induced HCC was preceded at 4-week feeding by a depletion of Toc and a remarkable increase of phosphatidylcholine hydroperoxide (PCOOH) in the livers of CDE mice. When HCC was prominent in CDE mice, PCOOH was still elevated. Mouse glutathione S-transferase (GST) M II isozyme, which is related to rat GST-P form, a positive marker for rat hepatic preneoplastic and neoplastic lesions, revealed an inverse histochemical pattern as that seen in rats (i.e., the HCC lesions tended to decreased staining). The aforementioned results taken together indicate that decreases in Toc and enhanced PC peroxidation are important events in CDE-induced mice liver tumors.
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PMID:Phosphatidylcholine peroxidation and liver cancer in mice fed a choline-deficient diet with ethionine. 842 21

Phenobarbital is an inducer of xenobiotic-metabolizing enzymes, such as cytochrome P-450, glutathione S-transferases (GSTs) and NAD(P)H:quinone reductase, as well as being a promoter of hepatocarcinogenesis. The molecular mechanisms regulating these biological activities are, however, unknown. In this paper we show that induction by phenobarbital of GST Ya and quinone reductase gene expression is mediated by regulatory elements, EpRE and ARE respectively, which are composed of two adjacent AP-1-like binding sites. EpRE was recently found to be activated by a Fos/Jun heterodimeric complex (AP-1). Here we show that phenobarbital induces an increase in AP-1 binding activity in nuclear extracts of cultured hepatoma cells. Furthermore, we observe that the induction of chloramphenicol acetyltransferase (CAT) activity from an EpRE Ya-cat gene construct and of AP-1 binding activity by phenobarbital is inhibited by the thiol compounds N-acetyl-L-cysteine and glutathione. These results suggest that the phenobarbital induction of AP-1 activity, leading to the AP-1-mediated transcriptional activation of the GST Ya and quinone reductase genes, may involve production of reactive oxygen species and an increase in intracellular oxidant levels, which is prevented by thiol compounds. In view of the involvement of AP-1 in the control of cell proliferation and transformation, the induction by phenobarbital of AP-1 binding activity observed here provides a possible molecular mechanism for the tumour-promoting activity of this drug.
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PMID:Phenobarbital induction of AP-1 binding activity mediates activation of glutathione S-transferase and quinone reductase gene expression. 845 90

Epidemiological studies show an increased risk of developing liver cancer among alcoholics. There is some agreement that ethanol itself is not carcinogenic, but it may enhance the tumorigenic process by inducing drug-metabolizing enzymes, suppression of the immune system or by affecting DNA repair enzymes. Precisely how ethanol predisposes or promotes the development of hepatoma is unknown. Hepatocarcinogenesis induced by a choline-deficient, ethionine-supplemented (CDE) diet produces extensive alteration of the liver architecture with the emergence and rapid proliferation of oval cells. This study examines whether chronic alcohol consumption induces the proliferation of oval cells. Oval cells induced in rats maintained on a 5% ethanol liquid diet (ELD) for up to 24 months, or fed a CDE diet for up to 4 weeks, are compared using a panel of liver-specific markers. In CDE-treated rats, oval cells staining positively for alpha-fetoprotein (AFP), pi-class glutathione S-transferase (pi GST), and the embryonic form of pyruvate kinase (M2-PK) are observed after 1 week. Similar cells are seen in ELD-treated rats after 2 months. Their numbers increase with time, and incorporation of [3H]thymidine confirms they are a dividing population. Acute damage induced by partial hepatectomy and CCI4 poisoning did not induce the appearance of oval cells. We conclude that chronic ethanol consumption induces oval cell proliferation. We suggest that, in addition to other proposed mechanisms, an alteration in cellular composition of the liver be considered as an explanation for the increased incidence of liver cancer among alcoholics.
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PMID:Appearance of oval cells in the liver of rats after long-term exposure to ethanol. 855 34

Exposure of iron-loaded C57BL/10ScSn mice to the polychlorinated biphenyls (PCBs) mixture Aroclor 1254 in the diet (0.01%) for 5 weeks caused massive hepatic porphyria far greater than occurred with PCBs alone. This regime eventually causes hepatocellular carcinoma. Hepatic microsomal ethoxy-, pentoxy-, and benzyloxyresorufin dealkylase activities (respectively EROD, PROD, and BROD) catalyzed primarily by cytochrome P4501A1 and 2B isoenzymes were markedly induced after 2 weeks of diet (when no porphyria had developed) but showed little effect of iron. EROD activity in the nuclear membrane was also induced by the PCBs as was CYP1A1 protein when shown by immunoblotting. Nuclear dealkylase activities of PCBs-treated mice were considerably less than microsomal activities but were stimulated by iron pretreatment. The mechanism of the iron-enhanced toxicity may be due to oxidative damage associated with chronic induction of CYP1A1 isoforms. Lucigenin-enhanced chemiluminescence (CL) by microsomes and nuclear membranes was used as a method to estimate their potential to form reactive oxygen species. Despite CL being induced by PCBs it was less with microsomes from iron-treated mice. In a comparison of a variety of inducers of microsomal cytochrome P450 there was no correlation between inducer, uroporphyrogenic agent, and intensity of CL. On the other hand, cytosolic glutathione S-transferase (GST) activities with 1-chloro-2,4-dinitrobenzene and 1,2-dichloro-4-nitrobenzene (DCNB) as substrates, were also induced by the PCBs mixture, the induction with DCNB being synergistically potentiated by iron pretreatment. Complementary results were observed by immunocytochemistry using anti alpha-GST antibody. In contrast, total glutathione peroxidase activity and selenium-dependent glutathione peroxidase activity were depressed by PCBs but particularly in mice also administered iron. The results illustrate that PCBs not only induce CYP1A1 in microsomes but also in the nuclear membrane, which may be of significance in the mechanism of the iron-enhanced carcinogenicity of these chemicals. The iron-enhanced induction of GST with accompanying depletion of glutathione peroxidase provides evidence for oxidative processes induced in vivo by the PCBs.
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PMID:Modulation by iron of hepatic microsomal and nuclear cytochrome P450, and cytosolic glutathione S-transferase and peroxidase in C57BL/10ScSn mice induced with polychlorinated biphenyls (Aroclor 1254). 856 Apr 83

The receptor for hepatocyte growth factor (HGF), a potent hepatocyte mitogen, is the product of the protooncogene c-met. In order to cast light on their significance for hepatocarcinogenesis, levels of both HGF and c-met mRNA were evaluated in rat livers during development of 2-acetylaminofluorene (2-AAF)-selected preneoplastic nodules and carcinomas following diethylnitrosamine (DEN) initiation. Rats were given a single i.p. injection of 200 mg/kg body wt DEN and, starting 2 weeks later, were administered 0.015% 2-AAF in the diet for up to 6 weeks. All rats were subjected to partial hepatectomy (PH) at week 3. Additional animals undergoing the DEN, 2-AAF and PH regimen were sacrificed at week 40 to allow evaluation of carcinomas. Oval cell proliferation, glutathione S-transferase placental form (GST-P)-positive preneoplastic lesion development and HGF and c-met mRNA levels were sequentially analyzed after PH. Numerous oval cells were observed 1 week after PH, but were remarkably reduced 2 weeks thereafter. The areas of GST-P-positive foci and nodules rapidly increased with time not only during 2-AAF feeding, but also to the same degree for at least 2 weeks after cessation of carcinogenic insult. Dot blot analysis showed HGF transcripts to be elevated after PH and during the selective growth conditions of 2-AAF feeding, dropping after cessation of carcinogenic insult. In the c-met transcript case transient increases were observed after PH, followed by a decrease. c-met over-expression in nodular livers did not correlate with the presence of 2-AAF or lesion development. In most hepatocellular carcinoma samples expression of both HGF and c-met mRNAs was below levels in non-neoplastic regions. These data suggest that HGF and c-met are directly involved in a paracrine growth pathway controlling proliferation in normal hepatocytes and oval cells, but not in preneoplastic and neoplastic cells.
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PMID:Expression of hepatocyte growth factor and c-met mRNAs during rat chemically induced hepatocarcinogenesis. 856 31


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