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)

Hemoglobin and myoglobin are a major source of dietary iron in man. Heme, separated from these hemoproteins by intraluminal proteolysis, is absorbed intact by the intestinal mucosa. The absorbed heme is cleaved in the mucosal cell releasing inorganic iron. Although this mucosal heme-splitting activity initially was ascribed to xanthine oxidase, we investigated the possibility that it is catalyzed by microsomal heme oxygenase, an enzyme which converts heme to bilirubin, CO, and inorganic iron. Microsomes prepared from rat intestinal mucosa contain enzymatic activity similar to that of heme oxygenase in liver and spleen. The intestinal enzyme requires NADPH; is completely inhibited by 50% CO; and produces bilirubin IX-alpha, identified spectrophotometrically and chromatographically. Moreover, duodenal heme oxygenase was shown to release inorganic (55)Fe from (55)Fe-heme. Along the intestinal tract, enzyme activity was found to be highest in the duodenum where hemoglobin iron absorption is reported to be most active. Furthermore, when rats were made iron deficient, duodenal heme oxygenase activity and hemoglobin-iron absorption rose to a comparable extent. Upon iron repletion of iron-deficient animals, duodenal enzyme activity returned towards control values. In contrast to heme oxygenase, duodenal xanthine oxidase activity fell sharply in iron deficiency and rose towards base line upon iron repletion. Our findings suggest that mucosal heme oxygenase catalyzes the cleavage of heme absorbed in the intestinal mucosa and thus plays an important role in the absorption of hemoglobin iron. The mechanisms controlling this intestinal enzyme activity and the enzyme's role in the overall regulation of hemoglobin-iron absorption remain to be defined.
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PMID:Intestinal absorption of hemoglobin iron-heme cleavage by mucosal heme oxygenase. 443 36

In heme degradation catalyzed by the reconstituted heme oxygenase system, 8 to 9 mol of dioxygen and 11 to 12 mol of NADPH were consumed per mol of hemin lost, and about half the amount of dioxygen consumed could be accounted for by the production of hydrogen peroxide, which accumulated in the reaction mixture. Production of hydrogen peroxide in the heme oxygenase reaction did not appear to be due to the bimolecular dismutation of superoxide anions but rather seemed to be due to dissociation of a "peroxo" species formed on heme or intermediates of heme degradation. The hydrogen peroxide produced appeared to cause a considerable degree of non-specific degradation of heme (not leading to the formation of biliverdin) and also caused an inactivation of heme oxygenase. By taking into account the amount of dioxygen incorporated into hydrogen peroxide and some other factors, it could be deduced that 3 mol of dioxygen is consumed for the formation of 1 mol of biliverdin in the heme oxygenase reaction.
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PMID:A stoichiometric study of heme degradation catalyzed by the reconstituted heme oxygenase system with special consideration of the production of hydrogen peroxide during the reaction. 630 26

A single, intraperitoneal injection of diethyldithiocarbamate (DDTC) to adult, male Sprague-Dawley rats decreased hepatic cytochrome P-450 (P-450) concentrations. This effect was dose-dependent over a range of 250 to 750 mg/kg and most prominent 24-36 hr after dosing. Depletion of hepatic glutathione (GSH) by diethylmaleate (DEM) administration significantly decreased P-450 8 hr after concurrent treatment with DDTC at a dose which given alone had little effect on P-450 concentrations. When hepatic microsomes were incubated with DDTC in the presence of NADPH, P-450 was converted to cytochrome P-420 (P-420). Similar incubations employing [35S]DDTC demonstrated strict NADPH-dependent binding of labeled sulfur to microsomal membranes, suggesting that diminished P-450 concentrations are related to the metabolic activation of DDTC. Addition of reduced GSH to incubation mixtures blocked the binding of 35S to microsomal membranes, as well as conversion of P-450 to P-420. DDTC inhibited NADPH-ADP3+ mediated peroxidation of microsomal lipids in vitro, suggesting that the effect of DDTC on P-450 does not result from stimulation of lipid peroxidation, but may be influenced by the levels of hepatic GSH. DDTC treatment 1 hr after P-450 was pulse labeled by an intravenous injection of [3H]delta-aminolevulinic acid resulted in a 2-fold increase in the rate of loss of radioactivity associated with membrane-bound P-450 heme during the next 20 hr. Within this time interval, hepatic heme oxygenase (HO) activity increased and at 8 hr after dosing was 7-fold greater than control values in the livers, but was unchanged in the kidneys and spleens of DDTC-treated animals. An elevation of hepatic delta-aminolevulinic acid synthetase (delta-ALAS) activity occurred at 8 and 24 hr after DDTC treatment. Since this enzyme is rate limiting in the biosynthesis of heme, its increased activity may represent a compensatory response to offset the DDTC-mediated loss of P-450 heme.
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PMID:Mechanisms of diethyldithiocarbamate-induced loss of cytochrome P-450 from rat liver. 631 Dec 17

Thallium (TlCl3) administration to rats produced a dose-dependent loss of hepatic NADPH-cytochrome c (P-450) reductase and microsomal mixed function oxidase activities within 2-4 hr following treatment. These changes occurred independently of apparent effects on microsomal heme or cytochrome P-450 content, both of which remained unchanged with respect to control levels despite transient inhibition of delta-aminolevulinic acid (ALA) synthetase and induction of heme oxygenase. These results are consistent with the recognized properties of thallium as both a flavoprotein antagonist and sulfhydryl inhibitor and differ uniquely from the action of other metals which impair mixed function oxidase activity through compromise of heme biosynthesis and heme depletion. The potential utility of thallium compounds in further evaluating the functional characteristics of NADPH-cytochrome c (P-450) reductase and its role in microsomal oxidative processes is suggested from these observations.
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PMID:Studies on the mechanisms of thallium-mediated inhibition of hepatic mixed function oxidase activity. Correlation with inhibition of NADPH-cytochrome c (P-450) reductase. 642 49

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

Leydig and Sertoli cells of the rat testes differ with respect to the activities of the enzymes of the heme and hemoprotein degradative pathway and in their responses to Cd2+ treatment. The microsomal heme oxygenase activity in the Leydig cell preparations was nearly 9- to 10-fold greater than in Sertoli cell preparations, but the characteristics of the enzyme appeared to be similar in both cell populations, as judged by the cofactor requirements and the inhibitory action of heme ligands. Differences between the two cell preparations also were detected in the activity of NADPH-cytochrome c (P-450) reductase and in the contents of cytochrome P-450 and heme, with Leydig cells possessing the higher values. The activities of the cytosolic biliverdin reductase were comparable in both cell preparations. The significantly higher levels of porphyrins and the activities of delta- aminoleuvinate synthetase and uroporphyrinogen-I synthetase suggest that Leydig cells constitute the primary site of heme and hemoprotein biosynthetic activities. The mode of regulation of heme oxygenase activity in the testes and in the liver was compared. The responses of heme oxygenase to Cd2+ treatment (20 mumoles/kg, 24 hr) in the two testicular cell populations were dissimilar and both differed from that of the liver. In Leydig cells, heme oxygenase activity was decreased dramatically, whereas in the liver the activity was greatly increased. Heme oxygenase activity in Sertoli cells was refractory to Cd2+. The Cd2+-mediated decrease in heme oxygenase activity in Leydig cells did not reflect a direct inhibitory action of Cd2+ on the enzyme or a decreased total content of the microsomal protein. The dissimilarity between the mode of regulation of heme metabolic activities in the testes, when determined in Leydig cells, and that in the liver involved the inability of bromobenzene to evoke an increase in heme oxygenase activity and the age-related changes in the activities of heme oxygenase and delta- aminoleuvinate synthetase. In contrast to heme oxygenase activity, the heme concentration in Sertoli cells was remarkably sensitive to Cd2+ treatment, where a 7-fold increase in heme concentration was observed. The same treatment caused only a 2-fold increase in heme concentration in Leydig cells. In the latter cells, however, the increase in heme concentration was accompanied by a marked reduction in cytochrome P-450 levels. The cytochrome could not be measured in Sertoli cell preparations.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Characterization of heme oxygenase activity in Leydig and Sertoli cells of the rat testes. Differential distribution of activity and response to cadmium. 642 20

Interferon inducers, poly I:poly C, endotoxin, hepatic RNA, and Tilorone, were administered to rats at different time points in relation to the onset of hyperoxic exposure (O2 greater than 97%). All interferon inducers tested significantly reduced the mortality of rats when compared with the control groups. In hyperoxia alone, malondialdehyde, a product of lipid peroxidation, was significantly increased and the microsomal enzyme NADPH cytochrome c reductase decreased as measured in the whole lung. With the administration of either endotoxin or poly I:poly C these two parameters remained within the range of control values. These data suggest that the administration of interferon inducers protects against hyperoxic microsomal damage. After the administration of these interferon inducers with or without hyperoxia the increased activity of heme oxygenase and marked reduction of the heme content of microsomes were demonstrated. Since cytochrome P-450 and b5 are the major hemoproteins of microsomes and the known source of oxygen-free radical generation, the results obtained in this study appear to indicate that the depression of the hemoprotein of microsomes by the administration of interferon inducers may be largely responsible for the protective effects of these agents against hyperoxia.
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PMID:Protective effect of interferon inducers against hyperoxic pulmonary damage. 654 2

Extracts of the phycocyanin-containing unicellular red alga, Cyanidium caldarium, catalyzed enzymatic cleavage of the heme macrocycle to form the linear tetrapyrrole bilin structure. This is the key first step in the branch of the tetrapyrrole biosynthetic pathway leading to phycobilin photosynthetic accessory pigments. A mixed-function oxidase mechanism, similar to the biliverdin-forming reaction catalyzed by animal cell-derived microsomal heme oxygenase, was indicated by requirements for O2 and a reduced pyridine nucleotide. To avoid enzymatic conversion of the bilin product to phycocyanobilins and subsequent degradation during incubation, mesoheme IX was substituted for the normal physiological substrate, protoheme IX. Mesobiliverdin IX alpha was identified as the primary incubation product by comparative reverse-phase high-pressure liquid chromatography and absorption spectrophotometry. The enzymatic nature of the reaction was indicated by the requirement for cell extract, absence of activity in boiled cell extract, high specificity for NADPH as cosubstrate, formation of the physiologically relevant IX alpha bilin isomer, and over 75% inhibition by 1 microM Sn-protoporphyrin, which has been reported to be a competitive inhibitor of animal microsomal heme oxygenase. On the other hand, coupled oxidation of mesoheme, catalyzed by ascorbate plus pyridine or myoglobin, yielded a mixture of ring-opening mesobiliverdin IX isomers, was not inhibited by Sn-protoporphyrin, and could not use NADPH as the reductant. Unlike the animal microsomal heme oxygenase, the algal reaction appeared to be catalyzed by a soluble enzyme that was not sedimentable by centrifugation for 1 h at 200,000g. Although NADPH was the preferred reductant, small amounts of activity were obtained with NADH or ascorbate. A portion of the activity was retained after gel filtration of the cell extract to remove low-molecular-weight components. Considerable stimulation of activity, particularly in preparations that had been subjected to gel filtration, was obtained by addition of ascorbate to the incubation mixture containing NADPH. The results indicate that C. caldarium possesses a true heme oxygenase system, with properties somewhat different from that catalyzing heme degradation in animals. Taken together with previous results indicating that biliverdin is a precursor to phycocyanobilin, the results suggest that algal heme oxygenase is a component of the phycobilin biosynthetic pathway.
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PMID:Enzymatic heme oxygenase activity in soluble extracts of the unicellular red alga, Cyanidium caldarium. 654 21

Mesoheme bound to heme oxygenase protein was easily degraded to mesobiliverdin by incubation with NADPH-cytochrome c reductase and NADPH. The features of mesoheme degradation were very similar to those of protoheme degradation catalyzed by the heme oxygenase system; an intermediate compound having its absorption maximum at 660 nm appeared in the couse of mesoheme degradation and this compound is presumably equivalent to the 688 nm compound which appears in the course of protoheme degradation. Hydroxymesoheme was chemically prepared and a complex of hydroxymesoheme and heme oxygenase was prepared. The complex was fairly stable in air, but when the complex was incubated with the NADPH-cytochrome c reductase system, the hydroxymesoheme bound to heme oxygenase was readily converted to mesobiliverdin through the 660 nm compound as an intermediate. It is evident that hydroxyheme is a real intermediate of heme degradation in the heme oxygenase reaction and that the 688 nm compound (or the 660 nm compound in the mesoheme system) is located between hydroxyheme and the biliverdin-iron chelate. The ferrous state of heme-iron may also be necessary for the onset of further oxidation of hydroxyheme.
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PMID:Degradation of mesoheme and hydroxymesoheme catalyzed by the heme oxygenase system: involvement of hydroxyheme in the sequence of heme catabolism. 689 22

A large number of synthetic iron porphyrins were enzymatically oxidized by a microsomal heme oxygenase preparation from rat liver. They all had in common two vicinal propionic acid residues at C6 and C7. Iron porphyrins of type I were not substrates of the enzyme. Iron porphyrins that carried electron-withdrawing substituents (acyl residues) at C2 and C4 were substrates of heme oxygenase, although the product yields were reduced. Several iron porphyrins, such as hemin XIII (4) and hem III (5), were better substrates of heme oxygenase than the natural substrate hemin IX (1). The enzymatic oxidation was selective for the alpha-methine bridge, and the alpha-biliverdins obtained were reduced by Biliverdin reductase to the corresponding alpha-bilirubins. Preincubation of the enzymatic system with hemin IX (1) and hemin XIII (4) in the absence of NADPH resulted in an inhibition of their oxidation. The iron-free porphyrins which carried two vicinal propionic acid residues at C6 and C7 were also found to be inhibitors of the enzymatic system when preincubated with the latter. The presence of hematochemin IX (18) suppressed the enzymatic oxidation of hemin IX (1).
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PMID:Specificity of heme oxygenase: a study with synthetic hemins. 689 13


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