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)

We report changes in free radical-metabolizing enzymes and the increased generation of lipid peroxides associated with extreme metal accumulation in the liver of the Long-Evans with cinnamon-like coat color (LEC) rat, a new mutant strain displaying hereditary hepatitis and subsequent hepatocellular carcinoma. The activity of free radical-metabolizing enzymes and lipid peroxides, and the concentration of metal in the liver were determined sequentially after birth. Mn-superoxide dismutase activity significantly increased immediately after the onset of hepatitis in LEC rats, whereas no remarkable change was observed in control rats. Cu, Zn-superoxide dismutase activity in LEC rats was similar to that in control rats. Glutathione reductase activity increased, while glutathione peroxidase activity was lower in LEC rats than in control rats throughout the observation periods. Lipid peroxides, estimated by thiobarbituric acid reaction, also increased 4- to 5-fold immediately after the onset of hepatitis in LEC rats. Copper concentration was 30- to 50-fold higher in the liver of LEC rats than in control rats, and the iron content also increased significantly before and after the onset of hepatitis. These findings suggested that an oxidant injury generated by toxic metals could be one of the factors responsible for hepatocellular damage in this unique hereditary hepatitis.
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PMID:Changes in free radical-metabolizing enzymes and lipid peroxides in the liver of Long-Evans with cinnamon-like coat color rats. 857 34

In erythrocytes of rats bearing Morris hepatoma 5123 the activities of superoxide dismutase, glutathione peroxidase and glutathione reductase as well as the level of reduced glutathione increased on the 10th day after transplantation of the tumor. In the second phase of the tumor growth (20 days after transplantation), the activities of glutathione peroxidase, glutathione reductase and the level of reduced glutathione in erythrocytes of the experimental animals were lower than in controls, whereas the activity of superoxide dismutase was at that time higher than in controls. On the other hand, the activity of catalase did not significantly differ from that found in healthy rats.
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PMID:The activities of superoxide dismutase, catalase, glutathione peroxidase and glutathione reductase in erythrocytes of rats with experimental neoplastic disease. 886 87

The content of reduced glutathione and of glutathione disulfide as well as the activities of glutathione reductase, glutathione peroxidase, glutathione S-transferases, catalase and superoxide dismutases were determined in human hepatoma Hep 3B cells in relation to free-radical toxicity in order to appreciate the defense capacities of these cells compared to data on normal hepatocytes. When Hep 3B cells were exposed to lindane, a known inducer of free-radical production, superoxide dismutase activity appeared as the best-adapted cellular parameter for early detection of the resulting free-radical toxicity.
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PMID:Assay of free-radical toxicity and antioxidant effect on the Hep 3B cell line: a test survey using lindane. 888 86

Two enzymatic mechanisms have been proposed for the metabolism of hydroperoxy-phospholipids: i) the combined action of phospholipase A2 and glutathione peroxidase, and/or ii) direct enzymatic reduction. The latter reaction may be catalyzed by selenium-dependent phospholipid hydroperoxide glutathione peroxidase and/or by glutathione S-transferase alpha. To study the pathway of this reaction, we used human hepatoma HepG2 cells into which was incorporated labeled, hydroperoxy-phospholipids. The major product of incorporated l-palmitoyl-2-(13-hydroperoxy-cis-9, trans-11-octadecadienoyl)-L-3-phosphatidylcholine was the corresponding hydroxy-phospholipid with no hydroxy- or hydroperoxy-fatty acids. The contributions to reduction of hydroperoxy-phospholipids in HepG2 cells from glutathione S-transferase Al and phospholipid hydroperoxide glutathione peroxidase were calculated to be 0.5% and 99.5%, respectively. Increasing selenium in the cell culture medium led to increases in selenium-dependent phospholipid hydroperoxide glutathione peroxidase activity but not in glutathione S-transferase alpha. This increase in the selenium-dependent enzyme was paralleled by a concomitant increase in the extent of reduction of the incorporated hydroperoxy-phospholipid. We conclude that the main metabolic fate of hydroperoxy-phospholipids in HepG2 cells is by direct reduction to hydroxy-phospholipids by phospholipid hydroperoxide glutathione peroxidase but also by glutathione S-transferase alpha, and that phospholipase A2/selenium-dependent glutathione peroxidase does not play a significant role in the reduction.
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PMID:Metabolism of hydroperoxy-phospholipids in human hepatoma HepG2 cells. 897 87

A resistant subline (AH130/5A) selected from rat hepatoma AH130 cells after exposure to adriamycin (ADM) showed remarkable resistance to multiple antitumor drugs, including mitomycin C (MMC) and porfiromycin (PFM). PFM, vinblastine (VLB), and ADM accumulated in AH130/5A far less than in the parent AH130 (AH130/P) cells. AH130/5A cells showed overexpression of P-glycoprotein (PGP), an increase in glutathione S-transferase activity, and a decrease in DT-diaphorase and glutathione peroxidase activity. The resistance to MMC and VLB of AH130/5A cells was partly reversed by H-87, an inhibitor of PGP. Buthionine sulfoximine, an inhibitor of glutathione synthase, did not affect the action of MMC. tert-Butylhydroquinone induced DT-diaphorase activity, increased PFM uptake, and enhanced the growth-inhibitory action of MMC in AH130/5A cells. Dicumarol, an inhibitor of DT-diaphorase, decreased PFM uptake and reduced the growth-inhibitory action of MMC in AH130/P cells. These results indicated that the adriamycin treatment of hepatoma cells caused multifactorial multidrug resistance involving a decrease in DT-diaphorase activity.
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PMID:Establishment by adriamycin exposure of multidrug-resistant rat ascites hepatoma AH130 cells showing low DT-diaphorase activity and high cross resistance to mitomycins. 904 1

Highly reactive oxyradicals can be generated in vitro by iron-catalyzed aerobic oxidation of synthetic and naturally occurring substances capable of enolization in aqueous medium. Of biological interest are alpha-hydroxy- and alpha-aminocarbonyls such as carbohydrates, 5-aminolevulinic acid, and aminoacetone which tautomerize to the corresponding enediols and enolamines and yield oxyradicals initiated by electron transfer to dioxygen. Free radicals have been implicated in several normal and pathological processes. We briefly review our hypothesis of an in vivo prooxidant role of 5-aminolevulinic acid (ALA), the heme precursor accumulated in several porphyric disorders (e.g., lead poisoning, acute intermittent porphyria (AIP), tyrosinosis). Accordingly, i) ALA undergoes transition metal-catalyzed oxidation to give O-2, H2O2 and HO.; ii) ALA induces iron release from ferritin, lipid peroxidation of cardiolipin-rich vesicles, single strand breaks in plasmid DNA, and guanosine oxidation in calf thymus DNA; iii) ALA causes Ca(2+)-mediated rat liver mitochondria permeabilization; iv) rats chronically treated with ALA exhibit increased glycolytic metabolism; v) brain extracts of ALA-treated rats reveal increased levels of thiobarbituric acid reactive substances, direct chemiluminescence intensity, carbonyl proteins, ferritin, and "free iron" and gamma-aminobutyric acid-receptor dissociation constant, and vi) patients with AIP and lead-exposed workers present augmented erythrocytic levels of the antioxidant enzymes superoxide dismutase and glutathione peroxidase. These data indicate the involvement of ALA-generated reactive species in the clinical manifestations (neuropathy, mental changes, muscle weakness, hepatoma) shared by the aforementioned inherited and acquired porphyric diseases.
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PMID:Oxidative stress in acute intermittent porphyria and lead poisoning may be triggered by 5-aminolevulinic acid. 907 Mar 73

The mechanism of localisation of metallothionein-I (MT-I) mRNA was studied in transfected cells by in situ hybridisation and cell fractionation. Hepatoma cells were transfected with the 5'-untranslated region and coding region of the beta-globin gene alone or linked to either the beta-globin 3'-untranslated region (3'-UTR) or the MT-I 3'-UTR. The wild-type beta-globin mRNA and the beta-globin mRNA lacking its native 3'-UTR were present in free and cytoskeletal-bound polysomes to a similar extent and showed no localisation. Chimaeric globin-metallothionein transcripts were significantly enriched in cytoskeletal-bound polysomes and were localised in the perinuclear cytoplasm. Chimaeric globin-metallothionein and wild-type globin transcripts were of similar stability. Chinese Hamster Ovary cells were transfected with constructs in which the MT-I 5'-untranslated region and coding sequences were linked to either the endogenous 3'-UTR or the glutathione peroxidase 3'-UTR. Wild-type MT-I transcripts were localised in the perinuclear cytoplasm but the chimaeric MT-I-glutathione peroxidase transcripts showed no distinct localisation. The results indicate that the 3'-UTR of MT-I mRNA contains a localisation signal which promotes both the association of the mRNA with the cytoskeleton and its perinuclear localisation.
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PMID:The 3' untranslated region plays a role in the targeting of metallothionein-I mRNA to the perinuclear cytoplasm and cytoskeletal-bound polysomes. 933 51

Erythropoietin (Epo) synthesis is suppressed in normoxia and stimulated in hypoxia. To test the hypothesis that the cellular H2O2 level is important in the control of Epo synthesis, we have studied effects of modulators of H2O2 generation and degradation on Epo production in human hepatic cell cultures (hepatoma lines HepG2 and Hep3B). In addition, we measured the activities of antioxidant enzymes (catalase, superoxide dismutase, glutathione peroxidase) in cultures following hypoxia exposure or H2O2 treatment. The results show that the formation of immunoreactive Epo was stimulated in normoxic cultures by treatment with exogenous catalase thus mimicking the effect of hypoxia (24 h incubation periods). Epo production was also stimulated when scavengers of reactive O2 species (tetramethylthiourea, dihydrorhodamine) were added to the cells. On the other hand, stimulators of H2O2 generation (xanthine oxidase, glucose oxidase, NADH, NADPH) lowered Epo production in hypoxic cultures. Hypoxia exposure decreased superoxide dismutase activity and H2O2 treatment reduced catalase activity thus influencing the endogenous antioxidant defense system. These findings support the concept that reactive O2 species, primarily H2O2, act as messengers in the O2-dependent control of the hepatic production of Epo. Changes in the cellular activities of antioxidant enzymes appear to play only a minor role in this process.
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PMID:Effects of modulators of the production and degradation of hydrogen peroxide on erythropoietin synthesis. 986 91

The recently described gastrointestinal glutathione peroxidase (GI-GPx) is the fourth member of the family of the selenoenzymes glutathione peroxidases (GPx). In contrast to the more uniform distribution of, for example, the classical glutathione peroxidase (cGPx), it is expressed exclusively in the gastrointestinal tract and has, therefore, been suggested to function as a primary barrier against alimentary hydroperoxides. In order to get an idea of its relative importance we investigated its position in the hierarchy of selenoprotein expression. The selenium-dependent expression of GI-GPx was analyzed in comparison with that of other GPx types at the level of mRNA and protein in HepG2 and CaCo-2 cells. Furthermore, the selenocysteine insertion sequence (SECIS) efficiencies of GI-GPx, phospholipid hydroperoxide glutathione peroxidase (PHGPx) and cGPx in response to selenium were determined by a reporter-gene assay in human hepatoma cells and baby hamster kidney cells. GI-GPx mRNA levels increased during selenium deficiency, whereas cGPx mRNA levels decreased and PHGPx mRNA levels remained almost unaffected. In cells grown in selenium-poor media, all GPx-types were low in both activity and immunochemical reactivity. Upon selenium repletion immunoreactive GI-GPx protein reached a plateau after 10 h, whereas cGPx started to be expressed at 24 h and did not reach its maximum level before 3 days. SECIS efficiencies decreased in the order PHGPx > cGPx > GI-GPx. The augmentation of SECIS efficiencies by selenium was highest for cGPx and intermediate for PHGPx, whereas it was marginal for GI-GPx. The high mRNA stability under selenium restriction, the speed of biosynthesis upon selenium repletion and the marginal effect of selenium on the SECIS efficiency indicate that of the GPx isotypes, GI-GPx ranks highest in the hierarchy of selenoproteins and point to a vital role of GI-GPx in the gastrointestinal tract.
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PMID:mRNA stability and selenocysteine insertion sequence efficiency rank gastrointestinal glutathione peroxidase high in the hierarchy of selenoproteins. 991 87

Cells cultivated under standard conditions were highly deficient in tocopherol, selenium, and glutathione peroxidase (GPx) activities. We investigated whether and to what extent the addition of different selenocompounds to growth media would alter biochemical, physiological, and pathophysiological parameters of cultured liver cells. Cellular uptake of selenium, GPx activities, and cytoprotection were measured and compared in human hepatoma cells (HepG2). Selenite and selenocystine were Se donors of high bioavailability (i.e., with these culture supplements, the increased Se uptake, induction of GPx isoenzymes, and protection of treated cells from lipid hydroperoxides were well correlated). In contrast, selenium from selenomethionine was incorporated into cellular proteins but had no effect on GPx activities or cytoprotection. The data show that not all selenium donors provide selenium, which is bioactivated to act as antioxidant. Thus, cellular selenium content, in general, did not correlate with cytoprotective activity of this trace element. However, cellular GPx activities at different times, with different concentrations, and with different Se donors always correlated with protection from lipid hydroperoxides and may, thus, represent a more reliable parameter to define adequate Se supply.
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PMID:Cytoprotection against lipid hydroperoxides correlates with increased glutathione peroxidase activities, but not selenium uptake from different selenocompounds. 1032 26


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