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 presence of cysteine and methionine groups together with an ability to bind long-chain fatty acid (LCFA) oxidation products makes liver fatty acid binding protein (L-FABP) an attractive candidate against hepatocellular oxidative stress. In this report, we show that pharmacological treatment directed at modulating L-FABP level affected hepatocellular oxidant status. L-FABP expressing 1548-hepatoma cells, treated with dexamethasone or clofibrate, decreased and increased intracellular L-FABP levels, respectively. Oxidative stress was induced by H2O2 incubation or hypoxia-reoxygenation. The fluorescent marker, dichlorofluorescein (DCF), was employed to measure intracellular reactive oxygen species (ROS). Hepatocellular damage was assessed by lactate dehydrogenase (LDH) level. Dexamethasone treatment resulted in a significant increase in DCF fluorescence with higher LDH release compared to control cells. Clofibrate treatment, however, resulted in a significant decrease in both parameters (p<0.05). Drug treatments did not affect cytosolic activities of glutathione peroxidase (GPx), superoxide dismutase (SOD), or catalase suggesting that the differences between treated and control cells may likely be associated with varying L-FABP levels. We conclude that L-FABP may act as an effective endogenous cytoprotectant against hepatocellular oxidative stress.
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PMID:Role of cytosolic liver fatty acid binding protein in hepatocellular oxidative stress: effect of dexamethasone and clofibrate treatment. 1692 18

Cyclophosphamide (CTX) is in the nitrogen mustard group of alkylating antineoplastic chemotherapeutic agents. It is one of the most frequently used antitumor agents for the treatment of a broad spectrum of human cancers. Thioredoxin reductase (TrxR) catalyze the NADPH-dependent reduction of thioredoxin and play an important role in multiple cellular events related to carcinogenesis including cell proliferation, apoptosis, and cell signaling. This enzyme represents a promising target for the development of cytostatic agents. The purpose of this study is to determine whether CTX could target TrxR in vivo. Lewis lung carcinoma and solid H22 hepatoma treated with 50-250 mg/kg CTX for 3 h lost TrxR activity in a dose-dependent fashion. Over 75% and 95% of TrxR activity was lost at the dose of 250 mg/kg. There was, however, a recovery of TrxR activity such that it attained normal levels by 120 h after a dose of 250 mg/kg. In addition, we found that CTX caused a preferential TrxR inhibition over other antioxidant enzymes, such as glutathione peroxidase, catalase, and superoxide dismutase. We also used ascites H22 cells to investigate cancer cells response after TrxR was inhibited by CTX in vivo since CTX is needed to be activated by liver cytochrome P450 enzymes. The time course and dose-dependent changes of cellular TrxR activity were similar with those in tumor tissue. CTX caused a dose-dependent cellular proliferation inhibition which was positively correlated with TrxR inhibition at 3 h. Furthermore, when 3 h CTX-treated cells with various TrxR backgrounds, harvested from ascites-bearing mice, were implanted into mice, the proliferations of these cells were again proportionally dependent on TrxR activity. The TrxR inhibition could thereby be considered as a crucial mechanism contributing to anticancer effect seen upon clinical use of CTX.
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PMID:Cyclophosphamide as a potent inhibitor of tumor thioredoxin reductase in vivo. 1715 7

Glutathione (GSH) is an important antioxidant that is involved in a multitude of cellular processes. However, in fish, GSH levels, turnover, and activity of associated enzymes are low when compared to those of mammals. To determine whether temperature influences the GSH antioxidant system in fish, and can explain the differences in GSH between fish and mammals, we examined the effects of acclimation temperature on total GSH (tGSH) levels and apparent half-life (as an estimate of turnover) in a rainbow trout hepatoma cell line (RTH-149), and GSH levels, and glutathione peroxidase (GPx) and reductase (GR) activity in the eurythermal killifish. Increasing incubation temperature decreased half-life and transiently increased levels of tGSH in RTH-149 cells. In killifish, increased acclimation temperature increased tGSH levels in the liver, brain and muscle, and increased hepatic GPx and GR activities. When the relationships between temperature and GSH half-life, levels and enzyme activity were extrapolated to 37 degrees C, temperature could only partially accounted for differences in the GSH antioxidant system in fish compared to mammals. The differences in the GSH antioxidant system between fish and mammals may not be solely due to temperature effects, but also to the increased metabolic cost of endothermy in mammals.
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PMID:Effects of acclimation and incubation temperature on the glutathione antioxidant system in killifish and RTH-149 cells. 1716 38

Glutathione (GSH) is one of the most important antioxidants in mammalian cells. It also plays an important role in chemical detoxification. Some evidence showed that polycyclic aromatic hydrocarbons, such as benzo[a]pyrene (B[a]P [50-32-8]), could increase GSH content as a defense mechanism against oxidative stress as well as to promote its detoxification. However, there has been very little study on clarifying the role GSH plays in antioxidation and detoxification actions. Therefore, the present study aims to analyze intracellular glutathione metabolism in the human hepatoma cells (HepG2) upon exposure to B[a]P. Exposure of the cells to B[a]P (1-100 microM) for 24 h did not cause significant cell death in this cell line. By selecting the sublethal concentration of 10 microM, B[a]P caused a significant increase in GSH and a small (13%) but significant decrease in glutathione reductase activity. However, there was no change in the activity of glutathione peroxidase, and no detectable increase in reactive oxygen species (ROS) production. Treatment with B[a]P caused up to 1.5 folds increase in gamma-glutamylcysteine synthatase (gamma-GCS) activity over control. Buthioneine sulfoximine (BSO), an inhibitor of gamma-GCS, could suppress GSH increase in a dose-dependent manner. Assessment of the oxidative state of the cells indicated that the increase in GSH caused the cells to become more reduced. Thus, the results concluded that cells were not suffering from oxidative stress at 24 h after treatment with 10 microM B[a]P. Upon analyzing the activities of detoxification enzymes, there was an increase in the activity of CYP1A subfamily monooxygenases and glutathione S-transferase. Both changes occurred prior to the changes in gamma-GCS activity and the increase in GSH. In summary, results of the present study demonstrate that B[a]P caused an activation of detoxification enzymes. The increase in intracellular GSH level was due to activation of gamma-GCS activities. Oxidative stress may not be an important risk factor for B[a]P (at 10 microM of up to 24 h) induced injury.
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PMID:Benzo[a]pyrene-induced elevation of GSH level protects against oxidative stress and enhances xenobiotic detoxification in human HepG2 cells. 1741 46

Soluble high-molecular weight fraction (named melanoidin) from coffee brew was isolated by ultrafiltration, subsequently digested by simulating a gastric plus pancreatic digestive condition and partly characterized by CZE, gel-filtration and browning. The objective of the present study was to investigate the potential protective effect of the coffee melanoidin submitted to gastrointestinal digestion on cell viability (lactate dehydrogenase leakage) and redox status of cultured human hepatoma HepG2 cells submitted to oxidative stress induced by tert-butylhydroperoxide (t-BOOH). Concentration of reduced glutathione (GSH) and malondialdehyde (MDA), generation of reactive oxygen species (ROS) and activity of antioxidant enzymes glutathione peroxidase (GPx) and reductase (GR) were used as markers of cellular oxidative status. Pretreatment of cultured HepG2 cells with 0.5-10 microg/mL digested coffee melanoidin (DCM) for 2 or 20 h completely prevented the increase in cell damage and GR and partly prevented the decrease of GSH and the increase of MDA and GPx evoked by t-BOOH in HepG2 cells. In contrast, increased ROS generation induced by t-BOOH was not prevented when cells were pretreated with DCM. The results show that treatment of HepG2 cells with concentrations of DCM within the expected physiological range confers the cells a significant protection against an oxidative insult.
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PMID:Effect of coffee melanoidin on human hepatoma HepG2 cells. Protection against oxidative stress induced by tert-butylhydroperoxide. 1742 63

Both selenium and green tea have been shown to have potential antitumor effects. Here we have investigated the anticarcinogenic effect of the selenium-enriched green tea extract (Se-TE) in a Kunming mice model transplanted with human hepatoma cells HepG2. Mice were assigned to 8 groups consisting of 10 mice each after tumor cell inoculation. The control group received only water, whereas the remaining groups received regular green tea extract (RT), Se-TE which was produced by fertilization with selenite on tea leaves, selenite, and RT + selenite. After the mice were fed intragastrically with these agents for 8 days, tumor growth in RT-, Se-TE-, and selenite-fed mice was significantly suppressed, compared with that in control mice (P < 0.001). Supplementation with Se-TEs and selenite was able to elevate mice blood and liver Se concentrations, but did not significantly enhance selenoprotein glutathione peroxidase and other antioxidant enzyme superoxide dismutase activity in mice blood and liver. These results suggest that the antitumor function of Se-TEs may be attributed to the oxidative stress induced by selenium and green tea components in a suitable selenium supplementation pathway.
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PMID:Anticarcinogenic activity of selenium-enriched green tea extracts in vivo. 1754 12

This is an extensive study in a defined initiation-promotion hepatocellular carcinoma model of hepatocarcinogenesis (in rats) in which many important marker enzymes and isoenzymes and 8-hydroxydeoxyguanosine formation have been studied together with two very important cellular proliferating genes, insulin-like growth factor II and c-raf.1, known for their role in hepatocellular cancer development. Experiments were carried out on hepatic tissues of male Sprague-Dawley rats. Variations in different enzyme/isoenzyme activities/contents/expression pattern and 8-hydroxydeoxyguanosine-positive cells were studied. Insulin-like growth factor II and c-raf.1 gene expressions were monitored. A direct shift with increase in size and numbers of lesions was found to occur in different experimental groups. In this study, glutathione peroxidase (1.14 and 1.46-fold) and reduced triphosphopyridine nucleotide (TPNH)-cytochrome-c-reductase (1.94 and 2.94-fold) activities, cytochrome b5 (1.57 and 3.28-fold) and P-450 contents (1.45 and 1.22-fold), glutathione content (1.27 and 1.45-fold) and superoxide dismutase and catalase (1.16 and 1.39-fold) activities in group A animals were found to be lower than those in initiation and promotion studies, respectively. 8-Hydroxydeoxyguanosine-positive nuclei count showed that oxidative damage of nuclear DNA enhanced with the progress of the disease. The insulin-like growth factor II expression was found to be predominant in hepatocellular carcinoma and in early preneoplastic lesions. Unlike insulin-like growth factor II, c-raf.1 expression was located in the late basophilic lesions associated with hepatocellular carcinoma. During the various stages of the development of hepatocellular carcinoma, the enzymes played a significant role in metabolizing carcinogens and thereby scavenging various toxic metabolites or free radicals produced. A sequence of cellular changes starting from the appearance of glycogen storage foci to basophilic foci leading to hepatocellular carcinoma via mixed cell foci varied the activity/content or expression pattern of the enzymes and isoenzymes and in 8-hydroxydeoxyguanosine formation. It has been established that c-raf.1-induced signaling pathways activated by insulin-like growth factor II is implicated in the late stage of development of cancer.
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PMID:Changes in the antioxidant defense and hepatic drug metabolizing enzyme and isoenzyme levels, 8-hydroxydeoxyguanosine formation and expressions of c-raf.1 and insulin-like growth factor II genes during the stages of development of hepatocellular carcinoma in rats. 1755 10

The objective of this study was to determine in a rat model of hepatocarcinoma (HCC) the effects of the antiangiogenic agent TNP-470 on antioxidant enzymes, including catalase (CAT), superoxide dismutases (Mn-SOD and Cu,Zn-SOD), and glutathione peroxidase (GPx). Tumor was induced in male Wistar rats by diethylnitrosamine and promoted by two-thirds hepatectomy plus acetaminofluorene administration. Experiments were carried out 28 weeks after initiating the treatment. TNP-470 was administered at 30 mg/kg, 2 times per week from weeks 20 to 28. Carcinomatous tissue was growing outside dysplastic nodules in rats with HCC. HCC caused oxidative stress demonstrated by increased lipid peroxidation and oxidized/reduced glutathione ratio that was accompanied by a reduced activity of antioxidant enzymes Cu,Zn-SOD, GPx, and CAT. In contrast, Mn-SOD activity and expression were higher in hepatocarcinoma than in control groups. These effects were absent in animals receiving TNP-470. No significant differences between untreated and TNP-470-treated rats were observed in the expression of the Cu,Zn-SOD, glutathione peroxidise, and CAT. We conclude that TNP-470 inhibits expression and activity of Mn-SOD induced by experimental hepatocarcinogenesis. Oxidative stress reduction by TNP-470 accounts for yet another anti-cancer effect of this molecule.
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PMID:Changes in the antioxidant system by TNP-470 in an in vivo model of hepatocarcinoma. 1776 72

Selenium methylselenocysteine (Se-MeSeCys) is a common selenocompound in the diet with a tested chemopreventive effect. This study investigated the potential protective effect of Se-MeSeCys against a chemical oxidative stress induced by tert-butyl hydroperoxide (t-BOOH) on human hepatoma HepG2 cells. Speciation of selenium derivatives by liquid chromatography-inductively coupled plasma mass spectrometry depicts Se-MeSeCys as the only selenocompound in the cell culture. Cell viability (lactate dehydrogenase) and markers of oxidative status--concentration of reduced glutathione (GSH) and malondialdehyde (MDA), generation of reactive oxygen species (ROS) and activity of the antioxidant enzymes glutathione peroxidase (GPx) and glutathione reductase (GR)--were evaluated. Pretreatment of cells with Se-MeSeCys for 20 h completely prevented the enhanced cell damage, MDA concentration and GR and GPx activity and the decreased GSH induced by t-BOOH but did not prevent increased ROS generation. The results show that treatment of HepG2 cells with concentrations of Se-MeSeCys in the nanomolar to micromolar range confers a significant protection against an oxidative insult.
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PMID:Selenium methylselenocysteine protects human hepatoma HepG2 cells against oxidative stress induced by tert-butyl hydroperoxide. 1795 20

An element/compound that acts as an antioxidant as well as, can increase the oxidative stress offers a new approach in differentiation therapy. Experiments were carried out to determine the effect of selenite on DNA damage and glutathione peroxidase (GPx) activity in N-nitrosodiethylamine (DEN) induced, phenobarbital promoted rat hepatoma. Supra-nutritional level of selenite (4 ppm) was supplemented at either, before-initiation/after-initiation and/or during entire period of the study. At the end of experiment period (20 weeks), extent of DNA damage (alkaline comet assay), selenium concentration, and GPx activity were assessed on nodular tissue (NL) cells, surrounding liver (SL) cells, and whole liver tissue (control) cells. Hepatic selenium level and GPx activity were decreased in DEN and PB-administered animals, whereas the DNA damage was found to be increased in both NL and SL cells compared with control group. However, the DNA damage is more in SL cells than in NL cells. Pre-supplementation of selenite did not show any difference in DNA (strand breaks) damage, selenium, and GPx activity. Increased hepatic selenium concentration and GPx activity were observed in both NL and SL cells in post-supplementation and entire period of selenite supplemented animals compared to DEN + PB treated animals. However, DNA damage was increased in NL but decreased in SL cells. Supplementation of selenite alone for 16 or 20 weeks had shown increased DNA damage, selenium concentration, and GPx activity compared to normal control animals. In summary, cancer bearing animals increased DNA damage and decreased Se level and GPx activity in NL and SL cells and other organs in cancer bearing animals, supplementation of Se further provoked DNA damage (no change in pretreatment) in NL cells, however it decreased DNA damage SL cells and other organs (kidney, lungs, and spleen). On the other hand Se levels and GPx activity were increased in NL and SL cells and other organs of Se-supplemented rats (no difference in group 3 animals). These results demonstrate that, in addition to chemopreventive and chemotherapeutic role of selenite, it also prevents cellular DNA damage induced in cancerous condition.
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PMID:Sodium selenite enhances glutathione peroxidase activity and DNA strand breaks in hepatoma induced by N-nitrosodiethylamine and promoted by phenobarbital. 1815 6


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