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)

Gold compounds are used clinically in rheumatoid arthritis therapy. Acute renal toxicity is observed in some patients receiving chrysotherapy. The present study addresses morphofunctional and biochemical changes in rat kidneys during the first 8 days following a single ip injection of gold sodium thiomalate (AuTM), one of the gold compounds presently in clinical use. Compared to controls, AuTM pretreatment resulted in increased urine output and elevated serum creatinine and urea nitrogen concentrations. Also, by Day 8, treated rats had decreased body weights and increased kidney weights. Postmortem examination on Day 1 showed pale and mottled kidneys and diffusely pale inner cortex. Microscopically, there was severe coagulative necrosis of the proximal tubular epithelium. Epithelial regeneration was prominent by Day 4 and was nearly complete by Day 8. The regenerating epithelium was hyperplastic with basophilic cytoplasm and pleomorphic nuclei. Alterations in renal heme biosynthesis and drug metabolism paralleled the morphologic changes. The activity of delta-aminolevulinic acid dehydratase and benzo[a]pyrene hydroxylase were inhibited on Days 1, 2, and 4 following AuTM administration. Decreases in monooxygenase activity were accompanied by decreases in renal cytochrome P-450 levels. In contrast, renal microsomal heme oxygenase activity was elevated 9.5-fold on Day 1 and 2.5-fold on Day 2. By Day 8, all renal enzymatic activities assayed for were similar to those obtained with untreated rats.
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PMID:Acute nephropathy induced by gold sodium thiomalate: alterations in renal heme metabolism and morphology. 311 10

The structural requirements for the inhibition of ferrochelatase by N-alkylated porphyrins were investigated and experiments carried out to explore the mechanism of enzyme inhibition. Three dicarboxylic porphyrins, all substrates of the enzyme, are strongly inhibitory when N-alkylated; in contrast, uroporphyrin and coproporphyrin (which are not substrates) do not inhibit after N-alkylation. Free carboxylic acid functions are required for inhibition, as the methyl ester derivatives are not themselves inhibitory. Porphyrins bearing the alkyl group on the pyrrole nitrogen of rings C and D are less effective inhibitors, particularly when zinc is chelated in the centre of the tetrapyrrole or the N-alkyl group is relatively large in size. The substituents at the 2- and 4-positions of the porphyrin system may also affect the inhibitory activity, particularly for the isomers with ring C and D alkylated. The zinc chelates of several N-alkylprotoporphyrins are inhibitory towards haem oxygenase, another haem-binding enzyme, and also in this case increasing the size of the alkyl group decreased the inhibitory activity, particularly for isomers with ring C or D alkylated. The inhibition could be reversed by prolonged incubation with excess porphyrin substrate, but dealkylation of the N-alkylporphyrin during enzyme inhibition could not be demonstrated. It is concluded (a) that N-alkylated dicarboxylic porphyrins compete reversibly with the porphyrin substrate for the enzyme active site and (b) that the structural and steric factors discussed above affect the inhibitory activity by modifying the affinity of the N-alkylporphyrin inhibitor for the enzyme.
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PMID:Studies on the inhibition of ferrochelatase by N-alkylated dicarboxylic porphyrins. Steric factors involved and evidence that the inhibition is reversible. 383 93

Pretreatment of rat hepatocytes with low-dose nitrogen oxide (addition of SNAP in vitro or induction of nitric oxide synthase in vitro or in vivo) imparts resistance to killing and decrease in aconitase and mitochondrial electron transfer from a second exposure to a higher dose of SNAP. Induction of this resistance is prevented by cycloheximide, indicating upregulation of protective protein(s). Ferritin levels are increased as are non-heme iron-NO EPR signals. Tin-protoporphyrin (SnPP) prevents protection, suggesting involvement of hsp32 (heme oxygenase) and/or guanylyl cyclase (GC). Cross-resistance to H2O2 killing is also observed, which is also prevented by cycloheximide and SnPP. Thus, hepatocytes possess inducible protective mechanisms against nitrogen oxide and reactive oxygen toxicity.
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PMID:Nitrogen oxide-induced autoprotection in isolated rat hepatocytes. 758 41

In in vitro systems haem oxygenase-1 (HO-1) mRNA increases after exposure to agents causing oxidative stress. We lowered cellular antioxidant defence systems in vivo by giving mice increasing doses (0.15 g/kg-1.6 g/kg) of DL-buthionine-(S,R)-sulphoximine (BSO), a specific inhibitor of glutathione synthesis. Maximum glutathione depletion (80%) coincided with maximum hepatic HO-1 mRNA accumulation (about 20 times), whereas with 50% depletion, accumulation was only doubled. It has been suggested that reactive oxygen and nitrogen intermediates are involved in hepatic toxicity of endotoxin (lipopolysaccharide, LPS); LPS even at low doses [0.1 mg/kg, intraperitoneally (i.p.)] induces HO-1 mRNA about 25-fold after 1 h. Hepatic glutathione depletion (respectively 40% and 80%) after a low (0.3 g/kg) or a high (1.6 g/kg) BSO dose, resulted in potentiation of the HO-1 mRNA accumulation induced by LPS (0.1 mg/kg, i.p.). In the absence of BSO, N-acetylcysteine (NAC) (1 g/kg orally) reduced LPS-induced HO-1 mRNA accumulation to one fourth. Under the same experimental conditions S-adenosylmethionine (SAM) was not effective. NAC also reduced HO-1 mRNA accumulation when administered to mice in which glutathione was depleted and its synthesis blocked by BSO (1.6 g/kg). Thus reactive oxygen intermediates are likely mediators of LPS-induced HO-1 mRNA accumulation, and glutathione content appears to be one of the factors regulating this accumulation in the liver. Our findings are compatible with the theory that HO-1 induction might have a protective function in vivo when defence mechanisms against oxidants are challenged.
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PMID:Mechanisms of endotoxin-induced haem oxygenase mRNA accumulation in mouse liver: synergism by glutathione depletion and protection by N-acetylcysteine. 799 83

The binding of ferrous and ferric hemes and manganese(II)- and manganese(III)-substituted hemes to heme oxygenase has been investigated by optical absorption, resonance Raman, and EPR spectroscopy. The results are consistent with the presence of a six-coordinate heme moiety ligated to an essential histidine ligand and a water molecule. The latter ionizes with a pKa approximately 8.0 to give a mixture of high-spin and low-spin six-coordinate hydroxo adducts. Addition of excess cyanide converts the heme to a hexacoordinate low-spin species. The resonance Raman spectrum of the ferrous heme-heme oxygenase complex and that of the Mn(II)protoporphyrin-heme oxygenase complex shows bands at 216 and 212 cm-1, respectively, that are assigned to the metal-histidine stretching mode. The EPR spectrum of the oxidized heme-heme oxygenase complex has a strongly axial signal with g parallel of approximately 6 and g perpendicular approximately 2. 14NO and 15NO adducts of ferrous heme-heme oxygenase exhibit EPR hyperfine splittings of approximately 20 and approximately 25 Gauss, respectively. In addition, both nitrosyl complexes show additional superhyperfine splittings of approximately 7 Gauss from spin-spin interaction with the proximal histidine nitrogen. The heme environment in the heme-heme oxygenase enzyme-substrate complex has spectroscopic properties similar to those of the heme in myoglobin. Hence, there is neither a strongly electron-donating fifth (proximal) ligand nor an electron-withdrawing network on the distal side of the heme moiety comparable to that for cytochromes P-450 and peroxidases. This observation has profound implications about the nature of the oxygen-activating process in the heme-->biliverdin reaction that are discussed in this paper.
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PMID:Resonance Raman and EPR spectroscopic studies on heme-heme oxygenase complexes. 826 Apr 99

Heme oxygenase (HO) catalyzes the first steps in the breakdown of heme to biliverdin and carbon monoxide. It is a membrane-bound protein that has been shown to exist in two isoforms, HO-1 and HO-2. Recently, a soluble, truncated form of rat HO-1 (rHO) lacking the 23 amino-acid membrane anchor has been expressed in E. coli. Extended X-ray absorption fine structure (EXAFS) data on ferric rHO and its fluoride derivative support assignment of the axial iron ligands as oxygen and/or nitrogen donors having distances similar to ferric myoglobin. The electronic absorption and magnetic circular dichroism (MCD) spectra of the ferric and ferrous protoheme complexes of rHO as well as various ligand adducts are very similar to the corresponding spectra of myoglobin. The present study is the first investigation of the heme-heme oxygenase complex with EXAFS and MCD spectroscopy and establishes that the proximal ligand to the heme in rHO is histidine. Furthermore, the close similarity between the electronic absorption and MCD spectra of ferric rHO and myoglobin over the pH range 6 to 10 is consistent with distal heme ligation of ferric rHO as a water molecule or hydroxide ion, depending on pH. Taken together and in conjunction with the results of earlier studies, EXAFS, electronic absorption, and MCD spectroscopy solidly establish that the ligands to the heme in rHO are identical to those in myoglobin, namely, histidine/H2O at low pH and histidine/OH at high pH.
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PMID:Ligation of the iron in the heme-heme oxygenase complex: X-ray absorption, electronic absorption and magnetic circular dichroism studies. 869 42

It has been known for a long time that heme oxygenase (HO) is a key enzyme in heme catabolism, and it was found to act as an oxidative-stress protein to produce carbon monoxide, which has similar actions to those of nitrogen monoxide. We examined transcriptional control of the HO gene in mouse M1 (myeloleukemia) cells during treatment with lipopolysaccharide (LPS; an oxidative reagent). Since the promoter region of this gene in human cells contains a 12-O-tetradecanoyl- phorbol-13-acetate(TPA)-responsive element (TRE) and a nuclear-factor-kappa B-responsive element. HO mRNA expression might be regulated by an oxidative activation pathway. We investigated activation of the HO gene after treatment of M1 cells with LPS. Upon treatment with LPS, H2O2 was produced, the nuclear proto-oncogenes fos and jun were activated, then the HO gene was activated. The extent of transcriptional activation of the fos, jun and HO genes in M1 cells treated with LPS was strongly reduced by a scavenger of oxygen radicals (N-acetyl-L-cysteine), but a specific inhibitor of protein kinase C only reduced transcriptional activation by 10-20%. These results suggest that LPS may be an oxidative reagent. Some oxidative reagents (e.g., H2O2) are strong activators of NF-kappa B, and therefore we treated M1 cells with H2O2. Essentially the same extends of transcriptional activation of the fos, jun and HO genes were observed as those observed after LPS treatment. Super-shift assays with DNA that contained the TRE motif revealed that the Fos and Jun proteins from nuclei of M1 cells treated with LPS and H2O2 bound weakly to the TRE motif, and, in assays with DNA that contained the NF-kappa B motif, nuclear protein from M1 cells treated with H2O2 or LPS bound strongly to the NF-kappa B motif. These results strongly suggest that the HO gene in M1 cells is mainly activated by LPS through oxidative activation of NF-kappa B due to production of H2O2.
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PMID:Lipopolysaccharide activates transcription of the heme oxygenase gene in mouse M1 cells through oxidative activation of nuclear factor kappa B. 877 98

It has long been known that heme oxygenase (HO) is a key enzyme in heme catabolism and recently it was also found to acts as an oxidative stress protein to produce carbon monoxide (CO), which has similar actions to those of nitrogen monoxide (NO). Therefore, we examined transcriptional control of the HO gene in mouse M1 (myeloleukemia) cells during their differentiation into macrophages. Since the promoter region of this gene is known to have a TPA-responsive element (TRE), its expression might be regulated by a C-kinase signal transduction pathway. Then we investigated the activation of the HO gene after treatment of M1 cells with TPA and inhibitors of C-kinase. When M1 cells were treated with TPA, they differentiated into macrophage-like cells. Upon treatment with TPA, H2O2 was produced first, the nuclear proto-oncogenes fos and jun were activated, and then the HO gene was activated. The extent of transcriptional activation of the fos, jun, and HO genes in M1 cells treated with TPA was reduced by a specific inhibitor of C-kinase and a scavenger of oxygen radicals. When M1 cells were treated with H2O2, essentially the same level of transcription of the HO gene was observed, but the extent of transcriptional activation of the fos and jun genes was about half of the treatment with TPA. Super-shift assays using the TRE of the HO gene revealed that the Fos and Jun proteins from nuclei of M1 cells treated with TPA bound to the TRE, and same assays using DNA with the NF-kappa B motif also revealed that the active NF-kappa B protein from M1 cells treated with H2O2 or TPA also bound to the corresponding motif. These results strongly suggest that the HO gene in M1 cells is activated by TPA through a production of H2O2, an oxidative activation pathway of NF-kappa B, and a signal-transduction pathway that involves C-kinase during the differentiation of macrophages that occurs upon treatment with TPA.
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PMID:Transcriptional control of the heme oxygenase gene in mouse M1 cells during their TPA-induced differentiation into macrophages. 887 3

Recent reports indicate the presence of two carbon monoxide (CO)-inducing enzymes, heme oxygenase (HO)-1 and -2 in airway smooth muscle. Generally HO-2 is considered to be a constitutive enzyme associated with various neuronal structures, whereas HO-1 can be induced by several factors, including hypoxia. Recent functional data indicate that exogenous CO can induce bronchodilation via a NO-independent, cyclic GMP-related mechanism. The aim of the present study was to investigate the potential role of CO as an endogenously produced airway messenger using an in vivo model of airway hypoxia. HO-1 and HO-2-like immunoreactivities were seen in airway smooth muscle along the bronchus and in the respiratory epithelium. The staining for HO-1 was relatively weak but consistent in all animals investigated. In contrast, the HO-2 staining was intense at all locations. After hypoxic stimulation, the staining for HO-1 and HO-2 was equally intense, indicating an up-regulation of the HO-1 expression. In another set up, anaesthetized, ventilated guinea-pigs were given a continuous infusion of histamine to increase total pulmonary resistance (R1). Hypoxic stimulation, induced by inhalation of 180 breaths of pure nitrogen (N2), resulted in a subsequent reduction in R1. Pretreatment with Rp-8Br-cGMPs, a cyclic GMP antagonist abolished more than 75% of this reduction, whereas L-NAME, an antagonist of NO synthesis, was without effect. Zinc protoporphyrin-IX (ZnPP), an inhibitor of HO, mimicked the effects of Rp-8Br-cGMPS. In conclusion, the present findings suggest a possible role for CO in the hypoxic regulation of airway tone.
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PMID:Carbon monoxide, a cyclic GMP-related messenger, involved in hypoxic bronchodilation in vivo. 1010 49

Peroxynitrite (ONOO-) is a potent oxidizing agent generated by the interaction of nitric oxide (NO) and the superoxide anion. In physiological solution, ONOO- rapidly decomposes to a hydroxyl radical, one of the most reactive free radicals, and nitrogen dioxide, another species able to cause oxidative damage. In the present study we investigated the effect of ONOO- on the expression of haem oxygenase-1 (HO-1), an inducible protein that is highly up-regulated by oxidative stress. Exposure of bovine aortic endothelial cells to ONOO- (250-1000 microM) produced a concentration-dependent increase in haem oxygenase activity and HO-1 protein expression. This effect was completely abolished by the ONOO- scavengers uric acid and N-acetylcysteine, and partly attenuated by 1,3-dimethyl-2-thiourea, a scavenger of hydroxyl radicals. ONOO- also produced a concentration-dependent increase in apoptosis and cytotoxicity, which were considerably decreased by uric acid and N-acetylcysteine. A 70% decrease in apoptosis was observed when cells were exposed to ONOO- in the presence of 10 microM tin protoporphyrin IX (SnPPIX), an inhibitor of haem oxygenase activity. When SnPPIX was added 5 min after ONOO-, apoptosis decreased by only 40%, which suggests that an interaction between ONOO- and the protoporphyrin occurs in our system. Increased haem oxygenase activity by pretreatment of cells with haemin resulted in elevated bilirubin production and was associated with a substantial decrease (35%) in ONOO--mediated apoptosis. These results indicate the ability of ONOO- to modulate the expression of the stress protein HO-1 and suggest that the haem oxygenase pathway contributes to protection against the cytotoxic action of ONOO-.
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PMID:Peroxynitrite induces haem oxygenase-1 in vascular endothelial cells: a link to apoptosis. 1021 13


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