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)

Studies on the enzymatic mechanism of microsomal heme oxygenase were made utilizing various porphyrins and metalloporphyrins of different ring substituents and central metal ions. Co-heme (cobalt protoporphyrin IX) was shown to be a substrate for the enzyme and the product of its oxidative metabolism was identified as the natural bile pigment, biliverdin IXalpha isomer. Metalloporphyrins, which do not bind molecular oxygen (Ni, Mn, and Sn protoporphyrin IX), were not substrates for heme oxygenase, although they could competitively inhibit oxidation of reactive substrates for the enzyme. The presence of lipophilic substitutents on pyrrole rings I and II, as well as a central metal atom, were required for the heme oxidation reaction to occur. The oxidative cleavage of Co-heme displayed typical characteristics of an enzyme-mediated reaction, and the oxidation of this substrate, as well as that of Fe-heme (iron protoporphyrin IX), could be supported with either reduced nicotinamide adenine dinucleotide phosphate or reduced nicotinamide adenine dinucleotide. A hypothesis is proposed on the mode of action of heme oxygenase in which the enzyme and its substrate are considered to form a "transitory" hemoprotein which can activate molecular oxygen for cleavage of the heme tetrapyrrole ring. In this formulation, heme as substrate for heme oxygenase is synonymous with heme as prosthetic group for the enzyme.
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PMID:Enzymatic oxidation of cobalt protoporphyrin IX: observations on the mechanism of heme oxygenase action. 83 94

The authors evaluated the in vitro and in vivo efficacy and photosensitizing effects of zinc deuteroporphyrin 2,4-bis glycol (ZnBG) as an inhibitor of adult Wistar rat tissue heme oxygenase (HO) activity and bilirubin production. Concentrations of 0.02-0.05 microM ZnBG inhibited the HO activity in postmitochondrial supernatants of liver, spleen, brain, and kidney by at least 50%. Administration of 4 mumole ZnBG/kg body weight to adult rats significantly reduced the total body carbon monoxide (CO) excretion, an index of bilirubin formation, from 1 to 6 hours posttreatment. At 6 hours posttreatment, the HO activity in postmitochondrial supernatants of the liver and spleen, but not of the brain, was significantly lowered. ZnBG also behaved as an in vitro photooxidizer by degrading, in the presence of cool white light, the reduced form of nicotinamide adenine dinucleotide phosphate and histidine to CO and other nonidentified products. ZnBG also enhanced the natural photodegradation of bilirubin. Furthermore, administration of ZnBG to 1-day-old neonatal rats caused mortality within 12 hours in light-exposed animals, with a lethal dose 50 of 23 microM/kg body weight.
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PMID:In vitro and in vivo characteristics of a heme oxygenase inhibitor: ZnBG. 177 16

Tin protoporphyrin (SnPP) and analogs are being studied as possible agents for the prevention of neonatal hyperbilirubinemia through inhibition of heme oxygenase. Because SnPP is a photosensitizer, we studied its role in the photogeneration of carbon monoxide (CO) from organic compounds in vitro. Generation of CO occurred in the presence of 5 microM SnPP and cool white light (19 muW/cm2/nm or 29 W/m2) from SnPP alone, human serum albumin, glucose, histidine, ethanolamine, medium-chain triglycerides, the reduced form of nicotinamide-adenine dinucleotide phosphate (NADPH), and human plasma. More detailed studies with human serum albumin and NADPH established that the photogeneration of CO is nearly linear with time and irradiance. It is curvilinear with respect to the SnPP concentration at the concentrations tested, and it is dependent on the presence of O2 in the reactor headspace. Cool white light generated less CO from human serum albumin and NADPH than equidistantly placed blue and green phototherapy light sources. Comparison of SnPP with other metalloporphyrin heme oxygenase inhibitors indicates that tin mesoporphyrin is most and zinc protoporphyrin least photoreactive.
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PMID:In vitro generation of carbon monoxide from organic molecules and synthetic metalloporphyrins mediated by light. 207 72

The effects of cannabidiol (CBD) and delta 9-tetrahydrocannabinol (delta 9-THC) on the synthesis and degradation of hepatic microsomal cytochrome P-450 were studied in mice. Cannabinoids used (10, 50 and 100 mg/kg, i.p.) did not affect delta-aminolevulinic acid synthetase activity in the liver. delta 9-THC-treatment (10, 50 and 100 mg/kg, i.p.) markedly stimulated heme oxygenase activity in hepatic 18000 X g supernatant fractions in a dose-dependent manner, whereas CBD-treatment was without effect. In vitro experiments, CBD and delta 9-THC (40 to 160 microM) markedly inhibited nicotinamide adenine dinucleotide phosphate (NADPH)-induced lipid peroxidation in hepatic microsomes. When CBD was incubated with the hepatic microsomes in the presence of an NADPH-generating system, cytochrome P-450 content decreased significantly. However, delta 9-THC showed no effects in similar experiments. The rate of decrease in the cytochrome P-450 content using CBD (160 microM) was 0.212 nmol/mg protein/20 min in microsomes from control mice. This value increased significantly in microsomes from phenobarbital-treated mice (0.792 nmol/mg protein/20 min) but not in those from 3-methylcholanthrene-treated mice (0.190 nmol/mg protein/20 min). The metabolic rate (per nmol cytochrome P-450) of CBD was also increased significantly by phenobarbital-treatment but not by 3-methylcholanthrene-treatment. These results suggest that CBD metabolites rather than CBD itself, play some role in the decreasing effect on cytochrome P-450 content in the hepatic microsomes in vitro, and that the microsomal formation of reactive metabolite of CBD is increased by phenobarbital-treatment.
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PMID:Effects of two cannabinoids on hepatic microsomal cytochrome P-450. 301 58

The effects of carbon disulfide (CS2) on the liver microsomal drug-metabolizing enzyme system and other enzyme activities were studied 1 hr after the oral administration of 3-300 mg/kg of CS2 in mice. Considerable decreases in drug-metabolizing enzyme activities (such as hydroxylation of aniline, O-dealkylation of p-nitroanisole, 7-ethoxycoumarin and 7-ethoxyresorufin, and N-demethylation of N,N-dimethylaniline), NADPH-cytochrome P-450 reductase (but not NADPH-cytochrome c reductase), and P-450-associated peroxidase activities were already observed at 3 and 30 mg/kg of CS2, dose dependently. At the same dosage levels, the magnitudes of microsomal spectral changes induced by aniline and nicotinamide (type 2 substrates), but not those induced by hexobarbital and SKF-525A (type 1 substrates), were also reduced to a considerable extent. The degrees of these alterations were all greater than that of the measurable loss of P-450 content, i.e. the loss of functional activity of P-450 was much greater than simply expected from the apparent decrease in the hemoprotein content. Cytochrome b5 content and NADH-ferricyanide reductase activity were unchanged at 30 and 300 mg/kg of CS2, although NADH-cytochrome c reductase activity was increased at the latter dose. The following enzyme activities did not change significantly at up to 300 mg/kg of CS2: flavin-containing monooxygenase, UDP-glucuronyl transferase, glucose-6-phosphatase and heme oxygenase in microsomes, and glutathione S-transferases in the soluble fraction. Microsomal conjugated diene levels and liver glutathione content were also unchanged. These observations support the theory that P-450 is a sensitive and selective site for CS2 action, where CS2 itself is bioactivated. It was also shown that the loss of P-450 was reversible after a single, or repeated, administration of CS2.
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PMID:Early, selective and reversible suppression of cytochrome P-450-dependent monooxygenase of liver microsomes following the administration of low doses of carbon disulfide in mice. 377 18

Cholestasis produced by bile duct ligation has been associated with decreased concentrations of hepatic microsomal cytochrome P450 and decreased hepatic microsomal oxidative drug metabolism. Bile duct ligation producing cholestasis results in a marked increase in hepatic microsomal heme oxygenase activity, with corresponding decreases in hepatic microsomal cytochrome P450 concentration, reduced form of nicotinamide adenine dinucleotide phosphate-cytochrome c reductase activity, and hepatic delta-aminolevulinic acid synthetase activity. As sham-operated rats also demonstrate a less prolonged decrease in cytochrome P450 concentration and reduced form of nicotinamide adenine dinucleotide phosphate-cytochrome c reductase activity, the metabolic effects of surgery and anesthesia must also be involved in these alterations in microsomal oxidative drug metabolism. The relative rate of hepatic cytochrome P450 synthesis and of degradation are both decreased after bile duct ligation. These data suggest that decreased hepatic microsomal cytochrome P450 concentrations in cholestasis are partly the result of decreased cytochrome P450 synthesis. Increased levels of heme oxygenase activity are not related to increased cytochrome P450 turnover, but may instead reflect enlargement and increased catabolism of a free heme pool resulting from decreased hemoprotein (cytochrome P450) synthesis.
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PMID:Effect of cholestasis produced by bile duct ligation on hepatic heme and hemoprotein metabolism in rats. 640 Dec 53

The effect of ethanol on maternal and neonatal hepatic heme and drug metabolizing systems was determined. Ethanol (16%, w/v) was administered orally as drinking solution to pregnant or lactating rats at different pre- and post-natal stages. The dams and pups were sacrificed on days 7, 14 and 21 after parturition, respectively. Ethanol administration to lactating rats from just after birth caused an appreciable decrease in the maternal and neonatal body and liver weights. In addition, the activities of nicotinamide adenine dinucleotide phosphate-cytochrome c reductase, nicotinamide adenine dinucleotide-cytochrome b5 reductase and heme oxygenase were significantly enhanced in the livers of neonates whose mothers were exposed to the ethanol during only first week of lactation, but those activities were not altered in the maternal livers. However, no remarkable alterations were observed in the contents of cytochrome P-450 and b5, and the activities of aminopyrine demethylase, aniline hydroxylase and delta-aminolevulinic acid synthetase in the livers of neonates from mothers who had received ethanol during lactation period or last week of gestation, although the activities of aminopyrine demethylase and aniline hydroxylase were enhanced significantly in lactating dams by ethanol consumption for 14 d after parturition.
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PMID:Influences of maternal ethanol intake on maternal and perinatal hepatic heme and drug metabolizing enzymes in rats. 667 77

We have investigated the expression of heme oxygenase (HO) in the rat kidney and the effects of HO-dependent heme metabolites on the apical 70-pS K+ channel in the thick ascending limb (TAL). Reverse transcriptase-PCR (RT-PCR) and Western blot analyses indicate expression of the constitutive HO form, HO-2, in the rat cortex and outer medulla. Patch-clamping showed that application of 10 microM chromium mesoporphyrin (CrMP), an inhibitor of HO, reversibly reduced the activity of the apical 70-pS K+ channel, defined by NPo, to 26% of the control value. In contrast, addition of 10 microM magnesium protoporphyrin had no significant effect on channel activity. HO involvement in regulation of the apical 70-pS K+ channel of the TAL, was further indicated by the addition of 10 microM heme-L-lysinate, which significantly stimulated the channel activity in cell-attached patches by 98%. The stimulatory effect of heme on channel activity was also observed in inside-out patches in the presence of 0.5-1 mM reduced nicotinamide adenine dinucleotide phosphate. This was completely abolished by 10 microM CrMP, suggesting that a HO-dependent metabolite of heme mediated the effect. This was further supported by exposure of the cytosolic membrane of inside-out patches to a carbon monoxide-bubbled bath solution, which increased channel activity. Moreover, carbon monoxide completely abolished the effect of 10 microM CrMP on the channel activity. In contrast, 10 microM biliverdin, another HO-dependent metabolite of heme, had no effect. We conclude that carbon monoxide produced from heme via an HO-dependent metabolic pathway stimulates the apical 70-pS K+ channel in the rat TAL.
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PMID:Carbon monoxide stimulates the apical 70-pS K+ channel of the rat thick ascending limb. 1019 68

It has recently been suggested that, in addition to nitric oxide (NO), carbon monoxide (CO) is an important gaseous messenger which might be involved in vertebrate olfactory transduction because its effects include activation of guanylyl cyclase and the formation of cGMP. As there is no information regarding the presence of heme oxygenase-2 -- the constitutive isoform of the heme oxygenase system -- in olfactory neurons of non-rodent species, we have investigated the distribution pattern of heme oxygenase-2 in the olfactory epithelium of the bovine, a representative of macrosmatics. Localization of nicotinamide adenine dinucleotide phosphate-diaphorase (NADPH-d) activity of the olfactory epithelium was compared with heme oxygenase-2 and NO synthase (NOS) immunoreactivities in order to obtain possible hints at functional significance. NADPH-d activity was particularly intense in apical dendrites of receptor neurons. It was also found in Bowman glands and intraepithelial duct cells. Less intense, discrete NADPH-d activity was present also at intermediate and basal levels of the olfactory epithelium, corresponding to the layer of receptor neuron somata and basal cells. While heme oxygenase-2 activity mainly occurred in neuronal perikarya, a very intense NOS immunoreactivity, exclusively for the inducible isoform, was detected in the apical dendrites. Ultrastructurally, NADPH-d histochemistry showed distinct labelling of membranes, in particular of endoplasmic reticulum, mitochondria and nucleus. The coincident localization of the moderate NADPH-d activity and heme oxygenase-2 immunoreactivity in receptor cell perikarya suggest a functional association between NADPH-cytochrome P450 reductase and heme oxygenase-2. In contrast, dendritic localization of NADPH-d activity is topically and possibly functionally related to the presence of the inducible isoform of NOS. The results suggest that both CO and NO may be generated in bovine receptor neurons and thus involved in odorant stimulation. Based on immunocytochemical localization of synthesizing enzymes, NO might be regarded as a direct regulator of transduction related processes while CO might act as a modulator of the initial signal.
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PMID:Heme oxygenase-2 and nitric oxide synthase immunoreactivity of bovine olfactory receptor neurons and a comparison with the distribution of NADPH-diaphorase staining. 1094 53

Occurrence of macrophage apoptosis has been implicated for the altered immune function found in an opiate milieu. In the present study, we evaluated the role of oxidative stress in morphine-induced macrophage apoptosis. Morphine promoted the apoptosis of macrophages. This effect of morphine was associated with the production of superoxide and nitric oxide (NO). Antioxidants provided protection against morphine-induced macrophage injury. In addition, diphenyleneiodonium chloride, an inhibitor of reduced nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activation, attenuated the proapoptotic effect of morphine. Antitransforming growth factor-beta (anti-TGF-beta) antibody and propranolol (an inhibitor of the phospholipase D pathway) inhibited morphine-induced superoxide generation as well as apoptosis. N'-Tetraacetic acid tetra (acetoxymethyl) ester, a calcium-chelating agent, inhibited morphine-induced apoptosis, whereas thapsigargin (a calcium agonist) stimulated macrophage apoptosis under basal as well as morphine-stimulated states. These studies suggest that morphine-induced macrophage apoptosis is mediated through downstream signaling involving TGF-beta and NO production. Moreover, there is NADPH oxidation activation involving phospholipase D and Ca(2+), leading to the generation of superoxide. In in vivo studies, administration of N-acetyl cysteine and preinduction of heme oxygenase activity and epoetin alpha prevented morphine-induced peritoneal macrophage apoptosis, thus further confirming the role of oxidative stress in morphine-induced macrophage apoptosis.
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PMID:Morphine-induced macrophage apoptosis: oxidative stress and strategies for modulation. 1503 69


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