Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:1.14.99.3 (heme oxygenase)
 4,196 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The report by Schacter et al. (J Biol Chem 247: 3601, 1972) that an antibody to NADPH-cytochrome c oxidoreductase inhibited NADPH-cytochrome c reductase and heme oxygenase activities in rat and pig liver and spleen microsomes demonstrated the role of this flavoprotein in microsomal heme oxygenation. Recent studies from other laboratories (Yoshida et al., J Biochem 75, 1187: 1974 and Bissell et al., Fed Proc 33: 1246, 1974) have strongly suggested that cytochrome P-450 is not involved in heme oxygenation. The availability of a homogeneous preparation of NADPH-cytochrome c reductase prompted us to test heme oxygenase activity in a system devoid of hemoprotein contamination. NADPH-cytochrome c reductase catalyzed biliverdin formation at a rate of 8.26 +/- 0.5 SEM nmole min-1mg-1 in the absence of biliverdin reductase. The rate of bilirubin formation in the presence of biliverdin reductase was less than 10% of the rate of biliverdin formation, suggesting that mixture of biliverdin isomers may be produced. Biliverdin production was potently (70--80%) inhibited by catalase, but was unaffected by superoxide dismutase. Epinephrine also inhibited heme oxygenation, presumably by utilizing O2. required for the formation of H2O2 by the reductase. By extrapolation, the NADPH oxidase activity due to NADPH-cytochrome c reductase can account for heme degradation occurring in microsomes. However, the specificity of ring scission at the IXalpha position must be due to another microsomal protein, perhaps the heme oxygenase of Yoshida et al., and not cytochrome P-450.
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PMID:The catalysis of heme degradation by purified NADPH-cytochrome C reductase in the absence of other microsomal proteins. 82 31

Cultured rat forebrain astrocytes contained significant amounts of immunostainable heme oxygenase-1 (HO-1) isozyme, whereas HO-1 was undetectable in spontaneously transformed rat astroglial cells (ATs). HO-1 was inducible in both cell types by heat shock and by submicromolar amounts of H2O2. Inhibition of RNA synthesis with actinomycin D or protein synthesis with cycloheximide resulted in the rapid loss of immunostainable heme oxygenase in astrocytes. Analysis of the primary structure of heme oxygenase suggests that it is a PEST protein, i.e., targeted for rapid turnover.
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PMID:Heme oxygenase is a heat shock protein and PEST protein in rat astroglial cells. 137 92

Thermotolerance, resistance to oxidative stress and induction of stress proteins were examined in a panel of 10 human tumour cell lines. An inverse relationship was indicated between intrinsic thermotolerance (cell survival after treatment at 43.5 degrees for 3 hr) and thermotolerance induced by pretreatment at 42.5 degrees for 30 min. Similar levels of induction of hsp 70 were found in cell lines with high or low levels of intrinsic thermotolerance; induction of other stress proteins could not be detected. Cell survival following treatment with H2O2 correlated with that following streptonigrin treatment (P < 0.05). Pretreatment with buthionine sulphoximine or diamide synergistically increased the toxicity of heat, H2O2 and streptonigrin whereas reduced glutathione had the reverse effect. No direct correlation was found, however, between tolerance to heat and to oxidative stress, and hsp 70 was not induced by the latter. The stress protein heme oxygenase, detected by immunoblotting with the monoclonal antibody HO, was induced by H2O2 in melanoma cell lines but not in HeLa. Cadmium and arsenite ions, however, readily induced heme oxygenase in HeLa, indicating that in these cells induction of heme oxygenase by oxidative stress involves a different mechanism. Overall, the results suggest that tolerance to heat or oxidative stress in these cell lines may not necessarily be associated with the induction of heat shock proteins or heme oxygenase but that cell survival after both types of stress depends to a certain extent on cellular sulphydryls.
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PMID:Relationships between thermotolerance, oxidative stress responses and induction of stress proteins in human tumour cell lines. 147 77

Phagocyte-mediated oxidant damage to vascular endothelium is likely involved in various vasculopathies including atherosclerosis and pulmonary leak syndromes such as adult respiratory distress syndrome. We have shown that heme, a hydrophobic iron chelate, is rapidly incorporated into endothelial cells where, after as little as 1 h, it markedly aggravates cytotoxicity engendered by polymorphonuclear leukocyte oxidants or hydrogen peroxide (H2O2). In contrast, however, if cultured endothelial cells are briefly pulsed with heme and then allowed to incubate for a prolonged period (16 h), the cells become highly resistant to oxidant-mediated injury and to the accumulation of endothelial lipid peroxidation products. This protection is associated with the induction within 4 h of mRNAs for both heme oxygenase and ferritin. After 16 h heme oxygenase and ferritin have increased approximately 50-fold and 10-fold, respectively. Differential induction of these proteins determined that ferritin is probably the ultimate cytoprotectant. Ferritin inhibits oxidant-mediated cytolysis in direct relation to its intracellular concentration. Apoferritin, when added to cultured endothelial cells, is taken up in a dose-responsive manner and appears as cytoplasmic granules by immunofluorescence; in a similar dose-responsive manner, added apoferritin protects endothelial cells from oxidant-mediated cytolysis. Conversely, a site-directed mutant of ferritin (heavy chain Glu62----Lys; His65----Gly) which lacks ferroxidase activity and is deficient in iron sequestering capacity, is completely ineffectual as a cytoprotectant. We conclude that endothelium and perhaps other cell types may be protected from oxidant damage through the iron sequestrant, ferritin.
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PMID:Ferritin: a cytoprotective antioxidant strategem of endothelium. 151 45

Interleukin 1 beta, potentiated by tumour necrosis factor alpha, is cytotoxic to pancreatic Beta cells in vitro. We have hypothesized that interleukin 1 beta induces oxygen free radicals in Beta cells. Since cytotoxicity induced by free radicals and by heat may activate the same cellular repair mechanism (the heat shock response), the aim of this study was to investigate the pattern of protein synthesis in isolated islets after exposure to interleukin 1 beta (150 pg/ml, 24 h), tumour necrosis factor alpha (50 ng/ml, 24 h) heat shock (43 degrees C, 30 min) and H2O2 (0.1 mmol/l, 20 min). By polyacrylamide gel electrophoresis, autoradiography, Western-blot analysis and partial peptide mapping of 35S-methionine labelled islets, interleukin 1 beta was found to induce a 73 kilodalton protein belonging to the heat shock protein family heat shock protein 70, a heat shock protein 90, and haem oxygenase. A minor induction of heat shock protein 73 and haem oxygenase was seen after H2O2. Interleukin 1 beta did not induce heat shock proteins in rat thyroid cells, rat mesangial cells or in human monocytes. Tumour necrosis factor alpha did not induce selective protein synthesis. Pre-exposure of islets to heat, tumour necrosis factor alpha, or H2O2 did not prevent the impairment of glucose-stimulated insulin release seen after 24 h of interleukin 1 beta exposure. The data are compatible with free radical induction by interleukin 1 beta. However, the heat shock response is not specific for oxidative injury, and previous studies have shown discrepant effects as to a protective effect of free radical scavengers against interleukin 1 beta-mediated beta-cytotoxicity.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Heat shock protein induction in rat pancreatic islets by recombinant human interleukin 1 beta. 188 86

H2O2, like other oxidants, is known to act as a mitogen at low concentrations in resting Balb/3T3 or mouse epidermal JB6 cells. We described previously that H2O2 induces some early response genes in Balb/3T3 cells. We extended these observations using another cell line, MC3T3 (mouse osteoblastic) cells by examination of transcriptional activity of these genes and by using inhibitors of protein kinases. H2O2 increased the expressions of c-fos, c-jun, egr-1 and JE genes which are known to be early response genes and are induced by mitogenic stimuli in many types of cells. Exogenous addition of H2O2 increased the mRNA levels of these genes, the kinetics of increase being similar to those of their inductions by a phorbol ester or serum. Nuclear run-on transcription showed that this induction occurred at the transcriptional level. H2O2 at 0.1-0.2 mM induced maximal expressions of c-fos and c-jun, whereas 0.3 mM H2O2 was required for induction of stress-induced heme oxygenase mRNA. The inductions of c-fos and c-jun were inhibited by 50 microM H7, a protein kinase inhibitor that is relatively specific for protein kinase C, but were not affected by H9, relatively specific for cAMP-dependent protein kinase. In cells pretreated with 12-O-tetradecanoylphorbol 13-acetate, however, in which protein kinase was supposed to be downregulated, H2O2 induced c-fos and heme oxygenase as efficiently as in untreated cells. H2O2 did not increase the phosphorylation of p80 protein, which is known to be a substrate for protein kinase C. Thus, H2O2 seemed to induce c-fos and c-jun by activating protein kinases distinct from protein kinase C. Activity of the chloramphenicol acetyltransferase gene under control of the serum-response element of human c-fos genes was increased by H2O2 treatment, whereas that under control of cAMP-response element was not affected. These results indicate that the inductions by H2O2 of c-fos and possibly other early response genes are mediated through activation of the serum-response element in their enhancer.
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PMID:Transcriptional activation of early-response genes by hydrogen peroxide in a mouse osteoblastic cell line. 191 80

Exposure of cells to elevated temperatures and other environmental stresses results in the expression of specific genes encoding the so-called heat shock proteins (HSPs). Since exogenous H2O2 induces in human monocytes the synthesis of HSPs, and previous induction of HSPs protects these cells from oxidative injury, we investigated whether HSP synthesis was also induced during generation of reactive oxygen species by the phagocyte itself during phagocytosis. As a model system, we analyzed the effects of erythrophagocytosis on protein synthesis by the human premonocytic line U937, in which phagocytosis is induced during differentiation with 1,25-dihydroxyvitamin D3. Exposure to whole erythrocytes, but not to erythrocyte ghosts, induced in the phagocytic cells only the synthesis of the 70- and 83- to 90-kDa HSPs and a 32-kDa oxidation-related stress protein identical by partial peptide mapping to heme oxygenase. The radioprotective aminothiol N-(2'-mercaptoethyl)-1,3-propanediamine (WR-1065), which can substitute for glutathione as hydrogen donor, prevented this induction. These results suggest that oxygen free radicals generated in the presence of hemoglobin-derived iron and consecutive glutathione depletion are involved in induction of stress protein synthesis during erythrophagocytosis. HSPs synthesized during phagocytosis may play a role in the phagocyte's defense mechanisms and in protective immunity.
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PMID:Erythrophagocytosis induces heat shock protein synthesis by human monocytes-macrophages. 215 67

The induction of heme oxygenase by both hydrogen peroxide and UVA (365 nm) radiation in normal human skin fibroblasts is prevented by prior treatment of cells with the specific iron chelators, o-phenanthroline or desferrioxamine. In addition, both iron chelators protected cells against the lethal effects of H2O2 treatment or UVA irradiation. We propose that the generation of the highly reactive hydroxyl radical by an iron catalyzed Fenton reaction is involved both in the induction of this stress response and, at least in part, in cell killing by the two treatments. These results are also consistent with the idea that the heme oxygenase gene is induced in response to oxidative stress and that its induction may constitute an inducible protective mechanism against oxidative damage induced by both hydrogen peroxide and UVA radiation.
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PMID:Induction of the heme oxygenase gene in human skin fibroblasts by hydrogen peroxide and UVA (365 nm) radiation: evidence for the involvement of the hydroxyl radical. 215 88

We report the identification of an NADH-dependent haem-degrading system in ox heart mitochondria. The activity was localized to the mitochondrial inner membrane, specifically associated with complex I (NADH:ubiquinone oxidoreductase). The mitochondrial NADH-dependent haem-degradation activity was highly effective and displayed a rate nearly 60% higher than that of the microsomal activity. The following observations suggested the enzymic nature of the activity: (i) haem degradation by complex I did not proceed upon exposure to elevated temperature and extremes of pH; (ii) it displayed substrate specificity; (iii) it was inhibited by a substrate analogue; and (iv) it showed a cofactor requirement. Moreover, the activity was distinctly different from the ascorbate-mediated haem-degradation activity. Also, complex I differed from the microsomal NADPH:cytochrome c (P-450) reductase inasmuch as the formation of an effective interaction with the microsomal haem oxygenase could not be detected. Addition of purified haem oxygenase to complex I neither influenced the rate of haem degradation nor resulted in the formation of biliverdin IX alpha. In contrast, addition of haem oxygenase to NADPH:cytochrome c (P-450) reductase enhanced the rate of haem degradation by nearly 8-fold, and more than 60% of the degraded haem could be accounted for as biliverdin IX alpha. The haem-degrading activity of complex I appeared to involve the activity of H2O2, as the reaction was inhibited by nearly 90% by catalase, and propentdyopents were detected as reaction products. Intact haemoproteins such as cytochrome c and myoglobin were not effective substrates. However, the haem undecapeptide of cytochrome c was degraded at a rate equal to that observed for haem. Haematohaem was degraded at a rate 50% lower than that observed for haem. It is suggested that the NADH-dependent haem-degradation system may have a biological role in the regulation of the concentration of respiratory haemoproteins and the disposition of the aberrant forms of the mitochondrial haemoproteins.
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PMID:Characterization of an NADH-dependent haem-degrading system in ox heart mitochondria. 312 Jun 97

Male mice were fed a diet containing less than 0.01 ppm selenium (Se-) for 6 months. A control group received the same diet containing 0.5 ppm selenium (Se+). In the livers of the Se- animals a drastic decrease in glutathione peroxidase (GSH-Px) activity was observed. It reached undetectable levels after 17 days of the Se- diet. At that time, GSH-transferase activity began to increase significantly, followed by changes in many other enzyme activities. After the 60th day, these enzyme modulations had reached a plateau with the following percentage changes compared to controls: GSH-transferases: 320% (1,2-dichloro-4-nitrobenzene), 218% (1-chloro-2,4-dinitrobenzene); glutathione reductase: 160%; ethoxycoumarin deethylase: 330%; cytochrome P-450-hydroperoxidase: 230%; heme oxygenase: 240%; UDP-glucuronyltransferase: 200%; GSH-thioltransferase: 64%; sulphotransferase: 62%; NADPH-cytochrome-P-450-reductase: 65%; flavin-containing mono-oxygenase: 57%. No significant changes were observed for GSH-transferase activity assayed with ethacrynic acid or for microsomal H2O2 formation and aniline hydroxylase activity. In single-pulse repletion experiments by injection of 250 micrograms selenium/kg body wt, different individual time constants for the recovery process of the enzymatic perturbations were observed. The half-times for the recovery ranged from 5.7 hr for the microsomal NADPH-cytochrome-P-450 reductase to over 29 hr for GSH-Px up to 44 hr for part of the GSH-transferase activity. 250 micrograms selenium/kg body wt were needed to restore 50% of GSH-Px activity in the long-term Se- mice compared to Se+ controls. All other enzymatic changes in the Se- mice needed a dose of 7 micrograms selenium/kg body wt for 50% restorage . The results demonstrate that processes other than those related to GSH-Px take place in a later phase of selenium deficiency in mouse liver with a chronologically common beginning. The different repletion and depletion kinetics as well as the different need of these processes for the trace element are discussed with respect to the existence of two separate selenium pools.
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PMID:Selenium and drug metabolism--II. Independence of glutathione peroxidase and reversibility of hepatic enzyme modulations in deficient mice. 642 18


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