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 murine aromatic hydrocarbon ([Ah]) gene battery consists of at least six genes that code for two functionalizing (Phase I) enzymes and four non-functionalizing (Phase II) enzymes. These enzymes are induced by compounds such as aromatic hydrocarbons and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) that bind to the cytosolic Ah receptor protein. Studies in rodents indicate that certain enzymes of this battery, namely cytochrome P4501A1 (CYP1A1), UDP-glucuronosyltransferase (UGT1*06) and NAD(P)H: quinone acceptor oxidoreductase (NMO1) are induced by the synthetic antioxidant 5,10-dihydroindeno[1,2-b]indole (DHII). The induction of [Ah] gene battery enzymes and the levels of reduced glutathione (GSH) were examined in mouse Hepa-1c1c7 hepatoma wild-type cells (wt), a CYP1A1 metabolism-deficient mutant (c37) and an Ah receptor nuclear translocation-defective mutant (c4). DHII and TCDD increased the activities of ethoxyresorufin O-deethylase, an indicator of CYP1A1 activity, as well as NMO1, UGT1*06, cytosolic aldehyde dehydrogenase class 3 and glutathione S-transferase form A1 in wt cells, but had little or no induction effect in c37 or c4 cells. DHII and TCDD differed in their effects on GSH levels; while DHII increased GSH levels 3-fold in wt, but not at all in c37 or c4 cells, TCDD had no effect on GSH levels in any cell type. However, GSH levels were enhanced in both wt and c4 cells by tert-butyl hydroquinone (TBHQ). L-Buthionine S,R-sulfoximine, an inhibitor of gamma-glutamylcysteine synthetase, prevented DHII-induced increases in wt cell GSH. The increase in GSH levels occurred after 8 h, while the induction of enzymes occurred within 4 h. The induction of the higher GSH levels in wt cells by DHII and TBHQ correlated with increases in intracellular levels of the GSH precursor thiol cysteine, as well as with increased activities of gamma-glutamylcysteine synthetase, the rate-limiting enzyme of GSH synthesis. However, TBHQ-mediated GSH increases in c4 cells were accompanied by increased gamma-glutamylcysteine synthetase activity with no change in intracellular cysteine concentration. The results suggest that DHII induction of [Ah] gene battery enzymes requires a functional Ah receptor, but not the functional gene product CYP1A1. Furthermore, metabolism, possibly via CYP1A1, appears to be required for DHII to enhance intracellular levels of cysteine and GCS activity that result in higher GSH levels.
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PMID:Regulation of [Ah] gene battery enzymes and glutathione levels by 5,10-dihydroindeno[1,2-b]indole in mouse hepatoma cell lines. 795 76

The addition of exogenous H2O2 inhibited hypoxia-induced erythropoietin (Epo) production in the human hepatoma cell line HepG2. Likewise, elevation of endogenous H2O2 levels by the addition of menadione or the catalase inhibitor, aminotriazole, dose-dependently lowered Epo production. The inhibitory effect of exogenous H2O2 on Epo formation could be completely overcome by co-incubation with catalase. When GSH levels in HepG2 cells were lowered, Epo production was more susceptible to H2O2-induced inhibition, indicating that H2O2 might affect thiol groups in regulatory proteins. Endogenous production of H2O2 in HepG2 cells was dependent on the pericellular O2 tension, being lowest under conditions of hypoxia. Our results support the hypothesis that an H2O2-generating haem protein might be part of the O2 sensor that controls Epo production. High H2O2 levels under conditions of normoxia suppress, whereas lower levels in hypoxic cells allow epo gene expression.
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PMID:Role of hydrogen peroxide in hypoxia-induced erythropoietin production. 798 Apr 10

The Long-Evans Cinnamon rat is a mutant strain that contracts hereditary hepatitis and, eventually, spontaneous hepatoma. Recently, abnormal copper accumulations in Long-Evans Cinnamon rat livers were shown to be genetically linked to the development of hepatitis. Because reduced glutathione and glutathione-related enzymes are known to play important roles in cellular resistance to transition metal toxicity, we determined the levels of reduced glutathione and glutathione-related enzymes in seven different tissues of Long-Evans Cinnamon and control Long-Evans Agouti rats. Of the enzymes examined, only hepatic glutathione peroxidase was markedly decreased in Long-Evans Cinnamon rats. Glutathione peroxidase content in the liver of Long-Evans Cinnamon rats was 39%, 53% and 58% of the control values at 9 (normal stage), 19 (acute hepatitis stage) and 27 (chronic hepatitis stage) wk of age, respectively. Northern-blot analysis revealed that messenger RNA levels of glutathione peroxidase in the livers of Long-Evans Cinnamon rats were about 40% of the control levels. The activity of glutathione S-transferase was slightly decreased in the livers of Long-Evans Cinnamon rats. These data suggest that the liver of the Long-Evans Cinnamon rat is poorly protected against active oxygen species, the production of which is enhanced in the presence of excess copper. Glutathione-reductase activity in the livers of Long-Evans Cinnamon rats increased to 166% and 148% of the control levels at 19 and 27 wk of age, respectively. No significant changes were observed in the activity of gamma-glutamylcysteine synthetase or in the content of total reduced glutathione in the liver of the Long-Evans Cinnamon rat.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Decreased expression of liver glutathione peroxidase in Long-Evans cinnamon mutant rats predisposed to hepatitis and hepatoma. 811 95

Cellular responses to copper, applied in concentrations varying from 0.5 to 200 microM Cu2+, were investigated in two different cell types: rat hepatoma cells (HTC) and primary cultured rat hepatocytes. Accumulation of 64Cu, copper (AAS) levels, cellular viability parameters (cell growth and proliferation, LDH leakage, total cell protein, K+ uptake, and ATP levels), and cell toxicity parameters (metallothionein (MT), glutathione (GSH) and superoxide dismutase (SOD)) were examined over 24 hr incubation periods. Accumulation of radiolabeled copper (applied copper concentrations: 15-200 microM Cu2+) showed a four-fold increase in HTC cells (0.88-3.45 nmol Cu/mg cell protein) and a three-fold increase in hepatocytes (4.94-14.66 nmol Cu/mg cell protein), although quantitative uptake in HTC cells was five times lower. Most of the copper accumulated in the hepatoma cells and hepatocytes was found predominantly in the particulate fraction (i.e., cell membranes and organelles), while only a small quantity was present in the soluble fraction (cell cytosol). Metallothionein concentrations in HTC cells were increased from 43 pmol/mg cell protein (0.5 microM Cu2+ application) up to 223 pmol/mg cell protein (200 microM Cu2+ application), whereas MT in rat hepatocytes were elevated from 139 pmol/mg cell protein to 546 pmol/mg cell protein over the same range of administered Cu2+. Metallothionein synthesis rendered both cell types well equipped to deal with increasing intracellular copper levels. In hepatocytes however, MT synthesis resulted in decreasing non-MT-associated copper levels in the cytosol for Cu administrations up to 100 microM. Above that point however, MT failed to stay in line with increasing cytosolic Cu levels, resulting in cytotoxic effects shown by changes in cell viability and GSH/SOD levels. In HTC cells MT synthesis suppressed the free Cu levels in the cytosol to below 0.1 nmol Cu/mg cell protein over the total range of copper concentrations applied. The results presented indicate that hepatoma HTC cells are more capable of dealing with high accumulated Cu levels than the better established rat hepatocytes. Furthermore, it is clear that comparison of these two cell types regarding their ability to respond on (sub)toxic Cu should be discussed with full consideration for the copper applications involved.
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PMID:Effects of copper on rat hepatoma HTC cells and primary cultured rat hepatocytes. 813 49

7-N-((2-([2-(gamma-L-Glutamylamino)ethyl]dithio)ethyl))mitomycin C (KW-2149) is an analogue of mitomycin C (MMC) and has prominent activities against various tumors. We studied the antitumor effects of KW-2149 in MMC-resistant variants of human colon carcinoma HT-29 (HT-29/MMC) and mouse hepatoma Hepa-I (C4, B13NBii1) cells, which are deficient in DT-diaphorase and cytochrome P450 reductase, respectively. These enzymes mediate the reductive activation of MMC in the cells. Although HT-29/MMC and C4, B13NBii1 cells showed significant resistance to MMC, they showed sensitivity tl KW-2149 comparable to their parental tumors, indicating that DT-diaphorase and cytochrome P450 reductase could not be involved in the activation of KW-2149. In studying the activation mechanism of KW-2149, we found that glutathione (GSH) and cysteine significantly enhanced the cytotoxicity of KW-2149 in HT-29 cells. The DNA adduct of KW-2149 was increased when HT-29 cells or the isolated nuclei of the cells were incubated with KW-2149 in the presence of physiological concentrations of GSH and cysteine. KW-2149 alkylated calf thymus DNA in the presence of GSH and cysteine in vitro. These results indicate that activation of KW-2149 by thiol molecules, unlike MMC, could be an important activation mechanism of KW-2149 to form DNA adduct and to exert its cytotoxicity. This is the reason why KW-2149 is effective against MMC-resistant tumors with deficiencies in the MMC activation enzymes.
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PMID:Nonenzymatic reductive activation of 7-N-((2-([2-(gamma-L-glutamylamino)ethyl]dithio)ethyl))mitomycin C by thiol molecules: a novel mitomycin C derivative effective on mitomycin C-resistant tumor cells. 816 87

Responses to zinc, applied in concentrations ranging from 3 to 200 microM Zn2+, were investigated in rat hepatoma tissue culture (HTC) cells and in primary cultured rat hepatocytes. The uptake of 65Zn, total Zn levels, cellular viability, metallothionein (MT) levels, superoxide dismutase (SOD) activities, and glutathione (GSH) levels were measured. Exposure at 50-200 microM Zn for 24 hr resulted in up to fivefold increases in intracellular Zn accumulation in hepatocytes and up to twofold increases in rat HTC cells. Hepatocytes increased their MT levels from 80 to 230 pmol MT/mg cell protein, whereas MT levels in HTC cells did not significantly change with increasing Zn applications. SOD activities rapidly increased in both cell types for applied [Zn] > 25 microM, eventually reaching up to two to three times the control SOD values at 200 microM applied Zn concentrations. GSH levels in hepatocytes increased to twice the control values, but gradually declined again with applied Zn concentrations > 100 microM, the latter probably due to progressive increases in GSH efflux. Cell viability tests indicated differences between effects on cellular metabolism (ATP levels) and effects on cellular condition (LDH leakage, 42K influx). The ATP data suggest significant but comparable Zn effects on cellular metabolism in both cell types, notwithstanding the large differences in cellular Zn, MT, and GSH levels. At comparable cytosolic total Zn levels, hepatocytes appeared more effectively protected against intracellular Zn toxicity by elevated MT and GSH levels. However, if considered with respect to applied Zn concentrations, at 200 microM cellular viability (LDH leakage) was more affected in hepatocytes than in HTC cells, the latter probably due to progressive sequestering of zinc on intracellular Zn-complexing compounds (MT, GSH) and subsequent accumulation of zinc in hepatocytes, in contrast with the absence of excessive Zn uptake by HTC cells. The overall results indicate that synthesis of (protective) cellular compounds like MT or GSH, although rendering cells resistant to metals, may--at the same time--result in relatively strong accumulation of potentially toxic metals.
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PMID:Effects of zinc on rat hepatoma HTC cells and primary cultured rat hepatocytes. 844 3

Effects of cadmium on hepatic glutathione (GSH) metabolism were characterized in a human-derived hepatoma cell line, Hep G2 cells. Intracellular GSH concentrations were significantly increased after incubation with cadmium at 5 and 10 microM for 24 and 48 hr. The rate of resynthesis of GSH after depleting cellular GSH by 0.5 mM of diethylmaleate was higher in cadmium (5 microM)-pretreated cells than that in untreated controls. GSH efflux from cadmium-pretreated cells was two-fold higher than that in untreated controls. On the other hand, incubation with cadmium at 5 and 10 microM for 60 min did not decrease GSH efflux. These findings suggest that increased intracellular GSH concentrations are attributed to enhanced synthesis of GSH under cadmium exposure, although the possibility of decreased intracellular consumption of GSH should further to be studied.
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PMID:Effects of cadmium on glutathione metabolism in Hep G2 cells. 858 39

Transcription factors AP-1 and NF-kappaB have been implicated in the inducible expression of a variety of genes in response to oxidative stress. Recently, based on the observation that butylated hydroxyanisole (BHA) and pyrrolidine dithiocarbamate (PDTC) induce AP-1 binding activity and AP-1-dependent gene expression and assuming that these compounds exert an antioxidant effect, it was claimed that AP-1 is an antioxidant-responsive factor. To determine whether AP-1 can be responsive to both oxidant and antioxidant, we examined the nature of BHA and PDTC inducing activity. Using EPR spectroscopy to detect semiquinone radicals, we demonstrate the autoxidation of BHA metabolite tert-butylhydroquinone (TBHQ) to tert-butylquinone. The kinetics of TBHQ-mediated generation of .OH radicals were monitored in intact hepatoma HepG2 cells by EPR spin trapping technique. Exogenous catalase inhibited the rate and amount of .OH radical formation and the induction of AP-1-mediated glutathione S-transferase (GST) Ya gene expression by BHA and TBHQ, thus indicating the intermediate formation of H2O2 in the metabolism of these chemicals. Furthermore, we show that the induction of AP-1 and NF-kappaB activities and GST Ya gene expression by BHA and TBHQ is due to a pro-oxidant activity, since this induction was inhibited by thiol compounds N-acetyl cysteine and GSH. Similarly, induction of AP-1 and GST Ya gene expression by PDTC was inhibited by N-acetyl cysteine and GSH. The present findings do not support the notion that the induction of AP-1 by BHA, TBHQ, or PDTC is an antioxidant response and demonstrate that both AP-1 and NF-kappaB activities are induced by oxygen radicals.
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PMID:Role of oxidants and antioxidants in the induction of AP-1, NF-kappaB, and glutathione S-transferase gene expression. 866 87

Effect of glutathione (GSH) depletion on paraquat (PQ) toxicity in the liver and kidneys of mice was examined. Glutamic-pyruvate transaminase (GPT) and blood urea nitrogen (BUN) levels in plasma of mice were hardly changed by treatment with 150 micro mol/kg of PQ. However, significant increases in the plasma GPT and BUN levels after PQ injection were observed in mice which were pretreated with L-buthionine-SR-sulfoximine (BSO), an inhibitor of GSH synthesis, at 4 hr prior to PQ administration. This result supports the previous observation that hepatotoxicity of PQ was enhanced in diethyl maleate-pretreated mice (Cagen and Gibson, 1977). In the present study, lipid peroxidation evaluated by thiobarbituric acid-reactive substances (TBA-RS) level in the liver of mice given PQ was elevated by pretreatment with BSO. Moreover, enhancement of PQ cytotoxicity by BSO pretreatment was also observed in cultured mouse hepatoma cell line (NCTC clone 1469). Vitamin E, an antioxidant, and Desferal, an iron chelator, significantly prevented mice from the BSO-enhanced hepato- and nephrotoxicity of PQ. These findings suggest that the tissues or cells of low GSH concentration are highly vulnerable to PQ toxicity and GSH may play a major role in diminishing the toxic action of PQ exerted through oxidative stress.
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PMID:Enhancement of paraquat toxicity by glutathione depletion in mice in vivo and in vitro. 872 Jan 62

We studied the effect of intracellular glutathione (GSH), which was known to conjugate readily with an alpha, beta-unsaturated carbonyl of 9-deoxy-delta 9,12-13,14-dihydroPGD2 (delta 12-PGJ2), on the cytotoxicity of delta 12-PGJ2. delta 12-PGJ2 caused DNA fragmentation in human hepatocellular carcinoma Hep 3B cells, which was blocked by cycloheximide (CHX). The delta 12-PGJ2-induced apoptosis was augmented by GSH depletion resulted from pretreatment with buthioninine sulfoximine (BSO), an inhibitor of gamma-glutamylcysteine synthetase. On the contrary, N-acetyl-cysteine (NAC), a precursor of cysteine, elevated the GSH level and protected cells from initiating apoptosis by delta 12-PGJ2. Sodium arsenite, a thiol-reactive agent, also induced apoptosis, which was potentiated or attenuated by BSO or NAC treatment respectively. These results suggest that the apoptosis-inducing activity of delta 12-PGJ2 is due to thiol-reactivity and intracellular GSH modulates the delta 12-PGJ2-induced apoptosis by regulating the accessibility of delta 12-PGJ2 to target proteins containing thiol groups.
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PMID:Intracellular glutathione level modulates the induction of apoptosis by delta 12-prostaglandin J2. 887 36


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