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 regulation of heme oxygenase activity in the developing neonate is essential to the control of bilirubin production as well as intracellular heme and hemoprotein metabolism. The coordinated activity of the microsomal enzymes, heme oxygenase and NADPH-cytochrome c (P450) reductase, and the cytosolic enzyme biliverdin reductase is responsible for the degradation of heme. The complete reaction sequence requires oxygen and NADPH, and produces bilirubin and carbon monoxide in equimolar amounts. Although heme oxygenase expresses a rather broad range of substrate affinities, the oxidative degradation of heme is exclusively alpha-specific. Heme oxygenase is found in several tissues, with significant activity levels in the liver, spleen, and erythropoeitic tissue. Heme oxygenase activity is inducible by heme and other metalloporphyrins, hormones, starvation, stress, toxins, and xenobiotics. Heme oxygenase induction is generally considered to be the result of an increased protein synthesis and gene transcription. This hypothesis is supported by recent studies of the heme oxygenase gene that identified inducer element binding sites responsive to metal administration, heat shock, and nutrient availability. In the developing fetus and neonate, hepatic heme oxygenase activity and mRNA levels are elevated above that of the adult. This suggests that the elevated heme catabolism observed in neonates may be associated with an increased transcription of the heme oxygenase gene. The apparent induction of hepatic heme oxygenase during the neonatal period is probably the result of tissue-specific and time-dependent transcriptional regulating factors including potentially hormones and heme. Several metalloporphyrins, such as the tin and zinc porphyrin complexes, inhibit heme oxygenase activity and thus have therapeutic potential for the treatment of neonatal jaundice. Recent studies suggest that the meso- and bis-glycol derivatives of these metalloporphyrins may be more potent inhibitors of heme oxygenase activity in vitro and in vivo than the protoporphyrin structures. As structural analogues of heme, however, these compounds may also have other less desirable effects on the regulation of heme and hemoprotein metabolism, particularly in the developing neonate.
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PMID:Developmental biology of heme oxygenase. 219 31

We have examined the toxicity of trans-platinum (trans-diamminedichloroplatinum II) to heme and hemoprotein metabolism in the kidney of glutathione (GSH)-depleted rats and compared it with that produced by cis-platinum. Unlike cis-platinum treatment (7.0 mg/kg, i.v.) which caused after 7 days significant increases in cytochromes P450 and b5, and a marked decrease in porphyrin content of the kidney, trans-platinum alone (7 mg/kg, i.v.) did not elicit notable changes in these variables when measured 1 or 7 days after treatment. Also, cis-platinum treatment significantly altered the heme degradation pathway by increasing the activity of heme oxygenase and decreasing that of biliverdin reductase; trans-platinum treatment did not elicit a response in these activities. However, when rats were given the inhibitor of GSH synthesis, D,L-buthionine-S,R-sulfoximine (BSO), the subsequent administration (2 hr later) of trans-platinum produced, in 1 day, the spectrum of responses that were mediated by cis-platinum after 7 days. In the kidneys of rats treated with BSO plus trans-platinum the concentration of platinum measured only about 50% of that detected in the kidneys of rats treated with trans-platinum alone. In the liver, trans-platinum by itself or in combination with BSO was ineffective in altering the measured variables of heme metabolism. The possibility that similarity between cis-platinum and trans-platinum plus BSO may extend to systems other than heme metabolism, e.g. GSH synthesis and degradation, was examined. cis-Platinum caused significant inhibition of both renal gamma-glutamyl synthetase and gamma-glutamyl transpeptidase after 7 days, but not after 1 day. Twenty-four hours after treatment, BSO + trans-platinum caused inhibition of gamma-glutamylcysteine synthetase activity, whereas this activity in animals treated with BSO alone had returned to control values. At this time point, neither oxidized glutathione (GSSG)-reductase nor gamma-glutamyl transpeptidase activity was affected by trans-platinum + BSO treatment. The findings suggest that GSH constitutes an important defense mechanism against trans-platinum alteration of heme metabolism and may play a role in cellular accumulation of the drug in an inactive complex. It is proposed that BSO treatment, despite resulting in a diminished intracellular concentration of trans-platinum, allows reaction of the metal complex with target molecules by virtue of its ability to deplete GSH.
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PMID:Promotion of trans-platinum in vivo effects on renal heme and hemoprotein metabolism by D,L-buthionine-S,R-sulfoximine. Possible role of glutathione. 233 13

Heme oxygenase has been purified to electrophoretic homogeneity from detergent solubilized adult human liver microsomes. Treatment of microsomes with Triton X-100, sodium cholate and subsequent batchwise DEAE-cellulose, 2', 5' ADP-sepharose 4B, Sepharose CLB and hydroxylapatite column resulted in 17% yield of the purified heme oxygenase. The reconsituted system of heme oxygenase, composed of heme oxygenase, NADPH cytochrome c (P450) reductase and biliverdin reductase was equiactive with 1 mM NADPH and 4 nM NADH and showed complete dependence on added heme for catalytic activity. The Km values for NADPH and NADH were .046 and .526 mM, respectively. While NADPH concentration was held constant, the Km value for heme was 1.01 microM with a specific activity of 583 unit/mg protein. The activity of the reconstituted heme oxygenase system was not affected by preincubation with heavy metals despite their inhibitory effect of NADPH cytochrome c (P450) reductase and biliverdin reductase. However, the metalloporphyrins of these heavy metals were found to be strong inhibitors of the reconsituted system with Ki values of 0.015, 0.6, 2.3 and 5 microM for Sn-, Co-, Zn- and Mg- protoporphyrins, respectively. Similarly, the sulfhydryl inactivating reagents, HgCl2, iodoacetamide and p-chloromercurylbenzoate, inhibited the reconstituted heme oxygenase activity. Rabbits were immunized with purified human liver heme oxygenase and the resulting antibody preparation was used to examine the species specificity of the enzyme. Microsomal protein with a molecular weight of 32,000 from rat and human liver as well as HepG2 cells were identified on dot and Western blots by their reaction with the anti-heme oxygenase similar to the purified enzyme protein. Anti-heme oxygenase precipitated quantitatively, the entire heme oxygenase of rat liver microsomes obtained from animals maintained on standard diet. The human bone marrow microsomal heme oxygenase activity was also quantitatively precipitated by this antibody. Antibody inhibition of rat and human heme xoygenase demonstrated a degree of conservation of both enzyme proteins between the species. As judged by Western blotting, the anti-heme oxygenase recognized only a single protein in spleen, liver, kidney, brain, heart, bone marrow, integtine and corneal epithelium. The human heme oxygenase cDNA was isolated by screening a cDNA library in the Okayama-Berg vector with a rat liver cDNA and was subjected to nucleotide sequence analysis. The deducted human heme oxygenase is also composed of 288 amino acids with a molecular mass of 32,800 Da.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Expression of heme oxygenase in hemopoiesis. 314 8

Coumarin 7-hydroxylase (COH) activity is catalyzed by the Cyp2a-5 gene product (CYP2A5 enzyme) in mice. Mouse hepatic CYP2A5 expression is often increased in conditions in which other P450 forms are repressed, e.g. after the administration of heavy metals and other toxic agents known to affect cellular heme balance. In this study, the effect of various porphyrinogenic chemicals on the expression CYP2A5 and the key enzymes in heme metabolism was studied. Administration of single doses of griseofulvin (1000 mg/kg), thioacetamide (10 mg/kg) and aminotriazole (1000 mg/kg) to DBA/2 and C57BL/6 mice produced up to 10-fold increases in hepatic COH catalytic activity. Dramatic, up to 130-fold increases in response to the inducers was observed in the amount of CYP2A5 steady-state mRNA. The mRNA contents of aminolevulinate synthase, ferrochelatase and heme oxygenase were also increased to a variable extent, possibly reflecting feed-back regulatory mechanisms. In D2 mice the CYP2A5 inducing effect of aminotriazole and thioacetamide, but not that of griseofulvin, pyrazole and phenobarbital, was abolished by exogenously administered heme arginate. In the B6 strain heme arginate treatment increased CYP2A5 expression but it did not affect the induction caused by porphyrinogenic agents. These results show that porphyrinogenic agents act as efficient inducers of CYP2A5, and suggest that regulation of the transcription of the Cyp2a-5 gene could in some instances involve heme-sensitive factors.
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PMID:Up-regulation of CYP2A5 expression by porphyrinogenic agents in mouse liver. 754 89

Although liver transplantation has been the subject of intensive investigation, comparatively little is known regarding the effects of this procedure on the metabolism of xenobiotics. The objective of the present study was to examine the effect of orthotopic liver transplantation on rat hepatic, pulmonary, and renal microsomal cytochrome P450 (P450) monooxygenase activity through the use of isozyme-selective substrates. Pulmonary microsomal P450 1A1 dependent 7-ethoxyresorufin O-deethylation (ERFD) activity increased over time in recipient rats, with maximal induction (750% of donor) observed after 21 days. Similarly, ERFD activity in renal microsomes was increased (200% of donor) after 21 days. Both pulmonary and renal microsomal P450 2B dependent 7-pentoxyresorufin O-depentylation (PRFD) activity was decreased (50 and 75% of donor) 1 day after transplantation but was essentially unchanged 3, 7, and 21 days after transplantation. Pulmonary and renal microsomal heme oxygenase activities were not significantly affected by liver transplantation. In contrast, total hepatic microsomal P450 concentrations were decreased maximally (to 45% of donor concentration) 7 days after transplantation and remained low (55% of donor) up to 21 days. Similarly, hepatic P450 1A dependent ERFD and P450 2B dependent PRFD activities were maximally depressed (20 and 25% of donor activities) after 7 days and remained low (75 and 30% of donor) up to 21 days after transplantation. The decreases in rates of hepatic P450 monooxygenation were accompanied by significant increases in microsomal heme oxygenase activity. The data presented in this study suggest the existence of generalized stress responses to inflammation that result in tissue- and isozyme-selective modulation of P450 monooxygenase activity.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Liver transplantation induces cytochrome P450 1A1 dependent monooxygenase activity in rat lung and kidney. 760 Apr 45

We compared the effects of 3 dipyridyl isomers, 2,2'-dipyridyl, 2,4'-dipyridyl and 4,4'-dipyridyl, on hepatic microsomal heme oxygenase and drug-metabolizing enzyme activities in male rats. 2,2'-Dipyridyl increased cytochrome P450 (P450) content at lower doses, but decreased with increasing dose levels. Immunoblot analysis revealed that 2,2'-dipyridyl did not induce both P450 1A1/2 and P450 2B1/2, in contrast to 2,4'- and 4,4'-dipyridyls, both of which were inducers of either P450 1A1/2 and/or P450 2B1/2. Some drug-metabolizing enzyme activities gradually declined with the increasing dose level of 2,2'-dipyridyl. 2,2'-Dipyridyl was able to induce hepatic microsomal heme oxygenase in a dose-dependent manner, but 2,4'- and 4,4'-dipyridyls did not, even at the highest dose (0.80 mmol/kg) examined. Treatment of rats with 2,2'-dipyridyl resulted in the increase of glutathione (GSH) content in a dose-dependent manner, but not 4-substituted isomers. A time course study with 2,2'-dipyridyl revealed that it produced a significant decrease in hepatic GSH content at early time periods (2-6 h) after its administration with an inverse increase in heme oxygenase activity. The present investigation has revealed that in contrast to the induction of P450 by 4-substituted dipyridyl compounds, 2,2'-dipyridyl is a novel inducer of hepatic microsomal heme oxygenase, together with the change in hepatic GSH content. This study would provide information on the differential effects of simple dipyridyl isomers on hepatic enzymes involved in heme and drug metabolism.
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PMID:Differential effects of 3 dipyridyl isomers on hepatic microsomal cytochrome P450 and heme oxygenase in rats. 772 46

The time- and dose-dependent accumulation of aluminum (Al) in liver and its effect on several hepatic systems were investigated in female Swiss-Webster mice given intraperitoneal (ip) Al lactate. A single dose of 50, 75, or 100 mg Al/kg produced significant depletion of hepatic glutathione (GSH) and cytochrome P450 (P450) and an increase in heme oxygenase (HO) activity when measured at 6 hr. However, no increase in hepatic malondialdehyde (MDA) was seen at this time. Using a dose of 100 mg Al/kg, Al rapidly accumulated in liver (0.29 +/- 0.03 vs 0.12 +/- 0.04 micrograms Al/mg protein at 6 hr). Hepatic GSH was significantly depleted at 2, 4, and 6 hr postdosing, HO activity was significantly increased at 6, 12, 24, 48, and 96 hr postdosing, hepatic cytochrome P450 was decreased at 12, 18, 24, and 48 hr postdosing, while hepatic MDA was not significantly elevated until 24 hr postdosing. Twenty-four hours following three daily doses of 50 mg Al/kg, HO activity was increased, P450 levels were depleted, and hepatic Al content was significantly increased, although hepatic MDA was unaffected. We conclude that parenteral Al produces a course of hepatic damage that begins with GSH depletion and proceeds through a sustained increase in HO activity, with cytochrome P450 loss being an early event and production of hepatic MDA being a late event.
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PMID:The temporal relationship between hepatic GSH loss, heme oxygenase induction, and cytochrome P450 loss following intraperitoneal aluminum administration to mice. 804 73

The effect of SnCl2 on the transcription of the heme oxygenase gene in spontaneously hypertensive rats was examined using cDNA for the rat heme oxygenase (HO-1). An increase in renal HO-1 mRNA levels was observed in response to SnCl2 treatment. Quantitative evaluation by scanning densitometry demonstrated a maximal increase in HO-1 mRNA 24-fold over control at 8 hours after SnCl2 administration. Nuclear runoff assay using isolated renal nuclei from SnCl2-treated rats revealed an active HO-1 gene transcription. Transcription of HO-1 in rat kidney was greatly increased within 3 hours of administration of SnCl2, as evidenced by the level of [alpha 32P]UTP incorporation into nuclear RNA. As a consequence of activation of the HO-1 gene transcription, renal enzyme activity increased eightfold at 16 hours after SnCl2, and reached maximal activity of 16-fold over control at 32 hours after injection. No significant change in cytochrome P450 fatty acid omega-hydroxylase (P450 4A) mRNA was observed after SnCl2 administration. Cytochrome P450-arachidonic acid omega/omega-1 hydroxylase(s) activity (formation of 20- and 19-HETE) was significantly reduced 24 hours after SnCl2 administration and remained lower than the control level 48 and 72 hours after injection. In addition, blood pressure was reduced from 151 +/- 2.5 mm Hg to 133 +/- 2.3 mm Hg after 48 hours of SnCl2 treatment. The reduction in blood pressure preceded natriuresis. It is concluded that SnCl2 induces activation of the HO-1 gene, which is followed by elevation in enzyme activity and a decrease in cytochrome P450-arachidonic acid omega-hydroxylase activity.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Tin-mediated heme oxygenase gene activation and cytochrome P450 arachidonate hydroxylase inhibition in spontaneously hypertensive rats. 816 Jul 7

1. Adjuvant-induced arthritic (AA) rats show a striking decrease in the level of cytochrome P450, a key microsomal haemoprotein involved in electron transport and drug metabolism in the liver. In the present study, we examined the relationship between the reduction of P450 content and haem metabolism in the liver of AA rats. 2. The activities of many enzymes catalyzing the biosynthesis of haem in the liver were significantly higher in AA rats than in normal rats, whereas only coproporphyrinogen oxidase activity in AA rats was markedly lower than that in normal rats. Furthermore, the activity of haem oxygenase, a key enzyme in the haem degradative pathway, increased significantly in AA rats. In addition, the degree of increase in the activity of this enzyme was clearly higher than that in the activity of 5-aminolevulinate synthase, a key enzyme in the haem synthetic pathway. 3. These results suggest that the reduction of live P450 content in AA rats is based on the lowering of liver haem content due to the combined action of the increased haem oxygenase activity and the decreased coproporphyrinogen oxidase activity. The changes in these enzyme activities were apparently suppressed by the continuous administration of indomethacin, which improved the arthritic states of the animals.
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PMID:Liver haem metabolism in adjuvant-induced arthritic rats. 917 82

Microsomal NADPH-cytochrome P450 reductase (CPR) is one of only two mammalian enzymes known to contain both FAD and FMN, the other being nitric-oxide synthase. CPR is a membrane-bound protein and catalyzes electron transfer from NADPH to all known microsomal cytochromes P450. The structure of rat liver CPR, expressed in Escherichia coli and solubilized by limited trypsinolysis, has been determined by x-ray crystallography at 2.6 A resolution. The molecule is composed of four structural domains: (from the N- to C- termini) the FMN-binding domain, the connecting domain, and the FAD- and NADPH-binding domains. The FMN-binding domain is similar to the structure of flavodoxin, whereas the two C-terminal dinucleotide-binding domains are similar to those of ferredoxin-NADP+ reductase (FNR). The connecting domain, situated between the FMN-binding and FNR-like domains, is responsible for the relative orientation of the other domains, ensuring the proper alignment of the two flavins necessary for efficient electron transfer. The two flavin isoalloxazine rings are juxtaposed, with the closest distance between them being about 4 A. The bowl-shaped surface near the FMN-binding site is likely the docking site of cytochrome c and the physiological redox partners, including cytochromes P450 and b5 and heme oxygenase.
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PMID:Three-dimensional structure of NADPH-cytochrome P450 reductase: prototype for FMN- and FAD-containing enzymes. 923 90


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