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)

1. The utilization of haem by rat liver apo-(tryptophan pyrrolase) under basal conditions and after enhancement of the enzyme activity by various mechanisms was studied under the influence of treatments affecting various aspects of liver haem metabolism. 2. These treatments were: benzoate and p-aminobenzoate as substrates of glycine acyltransferase, acetate as an inhibitor of 5-aminolaevulinate synthase activity, enhancement of 5-aminolaevulinate dehydratase by aluminium, destruction of haem and inhibition of ferrochelatase by porphyrogens, increased haem utilization by phenobarbitone and enhancement of haem oxygenase activity by metal cations. 3. The results show that the haem saturation of the apoenzyme is sensitive to all these treatments. 4. The possible usefulness of tryptophan pyrrolase in studying the regulation of liver haem is suggested.
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PMID:The effects of acetate, metal cations, phenobarbitone, porphyrogens and substrates of glycine acyltransferase on the utilization of haem by rat liver apo-(tryptophan pyrrolase). 88 Feb 48

After a single dose of cobaltous chloride there was a marked inhibition of liver 5-aminolaevulinate (5-ALA) synthetase (at 1 h) and this was followed in turn by a stimulation of haem oxygenase (at 3 h) and by a return of the synthetase activity to normal or above normal (at 17 h). Bile cannulation experiments were performed 1 and 17 h after administration of CoCl2. At 1 h there was a marked decrease in bile porphyrin content, no change in bile concentration of bilirubin, but a decrease in the conversion of [14C]-5-ALA to bilirubin and to liver haem. At 17 h, an the other hand, the bile excretion of both porphyrins and bilirubin was significantly greater than in controls and more radioactivity (from [14C]-5-ALA) appeared in the bile as bilirubin. It is concluded that the effects of cobalt on liver haem metabolism are complex and time-dependent. There is first inhibition of liver haem synthesis at two different steps of the pathway (synthesis of 5-ALA and conversion of 5-ALA to haem), with diversion of [14C]-5-ALA into a relatively stable liver pool different from haem; and at a later stage there is also an increase in the rate of liver haem degradation.
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PMID:The effect of cobaltous chloride on liver haem metabolism in the rat. Evidence for inhibition of haem synthesis and for increased haem degradation. 100 89

1. Heme synthesis from delta-aminolevulinic acid (delta-ALA) in freshly isolated rat hepatocytes was maximal at 100 microM with a rate of approx. 7 nmol being synthesized per g wet weight cells. 2. Approximately 8% of synthesized heme was converted to bilirubin and 50% of the newly synthesized bilirubin was conjugated. 3. The ratio of di to monoconjugate was approx. 2.5. Incorporation of delta-ALA into bilirubin was increased by additional delta-ALA, heme and was also doubled in cells isolated from animals treated with CoCl2. 4. Bilirubin formation was inhibited approx. 90% by in vitro treatment with heme oxygenase inhibitors zinc and tin protoporphyrin.
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PMID:Bilirubin production and conjugation from newly formed heme in isolated rat hepatocytes. 142 22

1. delta-Aminolevulinic acid synthetase (ALA-S), rhodanese and microsomal heme oxygenase (MHO), were quantitated in Cl4C induced regenerating mouse liver. 2. Maximal hepatomegalia was observed at 48 hr after i.p. injection of a single dose of the toxin. 3. ALA-S activity decreased on day 2, and then significantly increased (50%) between days 3 and 7, returning afterwards to control values. 4. Cytoplasmic rhodanese, as well as MHO activities, exhibited a clear correlation as compared with the ALA-S activity profile. 5. Porphyrin biosynthesis from precursor delta-aminolevulinic acid (ALA) was significantly increased even after 15 days of intoxication. 6. Present results would indicate that Cl4C is acting in a dual fashion.
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PMID:Regulation of heme pathway in regenerating mouse liver. 149 71

In the present study, the effect of chronic ethanol consumption in rats on the hepatic heme metabolism was investigated. Male Wistar rats were fed a nutritionally adequate liquid diet containing ethanol as 36% of the total calories for 5 weeks. After an overnight fast, the livers were excised and centrifuged to obtain mitochondrial and microsomal fractions. Chronic ethanol feeding of rats resulted in about 19% hepatomegaly as represented by the increased liver/body weight ratio. There was no difference in the mitochondrial protein content between the ethanol-treated and control rats, but the microsomal protein content was significantly increased in the ethanol-treated rats. Hepatic microsomal content of cytochrome P-450 (P-450) was markedly enhanced by chronic ethanol ingestion. Microsomal contents of cytochrome b5 (b5) and total heme were also increased to a lesser extent. After chronic ethanol abuse, the hepatic activity of delta-aminolevulinic acid (ALA) synthetase, which is a rate-limiting enzyme for heme production, was significantly increased and that of the heme oxygenase was slightly increased. These data indicate that ALA synthetase activity is induced by the negative feedback mechanism in order to compensate the depletion of heme caused by the utilization of heme for P-450. It is also speculated that, in response to excessive production of heme as described above, heme oxygenase activity is secondarily induced to regulate the amount of heme.
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PMID:Alterations in hepatic delta-aminolevulinic acid synthetase and heme oxygenase activities after chronic ethanol consumption in rats. 178 21

Earlier studies in this laboratory had implicated heme to function as a positive modulator of phenobarbitone-mediated activation of CYPIIB1/B2 gene transcription in rat liver. However, recent reports have indicated that succinylacetone, a specific inhibitor of delta-aminolevulinate dehydrase, does not affect this process. The present studies indicate that succinylacetone does inhibit the phenobarbitone-mediated increase in CYPIIB1/B2 mRNAs and their transcription in rat liver at early time points (45 min to 3 h), but the inhibition is not pronounced at later time points (16 h). Succinylacetone is a weaker inhibitor of heme biosynthesis than CoCl2, 3-amino-1,2,4-triazole, or thioacetamide used earlier in this laboratory. Succinylacetone induces delta-aminolevulinate synthase, whereas the other compounds depress the levels of the enzyme. There is a good correlation between the amount of freshly synthesized nuclear heme pool and the activation of CYPIIB1/B2 transcription by phenobarbitone. A model implicating a nuclear heme pool regulating the transcription of delta-aminolevulinate synthase, CYPIIB1/B2, and heme oxygenase genes is proposed.
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PMID:Involvement of heme in the transcriptional activation of CYPIIB1/B2 gene by phenobarbitone in rat liver--studies with succinylacetone. 189 87

Synthesis of the iron-storage protein ferritin is thought to be regulated at the translational level by the cytosolic content of chelatable iron. This response to iron is regulated by the iron-modulated binding to ferritin mRNAs of a repressor protein, the iron regulatory element-binding protein. From measurements made in a cell-free system, regulation of the iron regulatory element-binding protein has been recently suggested to involve direct interaction with hemin. The following observations on the synthesis of ferritin and of heme oxygenase (HO), the heme-degrading enzyme, in rat fibroblasts or hepatoma cells lead us to conclude that chelatable iron is a direct physiological regulator of ferritin synthesis in intact cells: (i) the inhibitor of heme degradation, tin mesoporphyrin IX, reduces the ability of exogenous hemin to induce ferritin synthesis but enhances HO synthesis; (ii) the iron chelator desferal suppresses the ability of hemin to induce synthesis of ferritin but not of HO; (iii) the heme synthesis inhibitor succinylacetone does not block iron induction of ferritin synthesis; (iv) there is no apparent relationship between the ability of various metalloporphyrins to inactivate the iron regulatory element-binding protein in cell-free extracts and their capacity to induce ferritin synthesis in intact cells; (v) administered inorganic iron significantly induces the synthesis of ferritin but not of HO; (vi) addition of delta-aminolevulinic acid to stimulate heme synthesis represses the ability of inorganic iron to induce ferritin synthesis while activating HO synthesis. Taken together, our results demonstrate that (i) release of iron by HO plays an essential role in the induction of ferritin synthesis by heme and (ii) chelatable iron can regulate ferritin synthesis independently of heme formation.
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PMID:Regulation of ferritin and heme oxygenase synthesis in rat fibroblasts by different forms of iron. 199 60

The administration of doxorubicin, an anti-tumor antibiotic, to rodents resulted in an increase in heme oxygenase activity and a decrease in delta-aminolevulinate (ALA) synthase activity and in cellular heme and cytochrome P450 content in liver. Sn-protoporphyrin, a potent inhibitor of heme degradation both in vitro and in vivo, when administered to rodents prior to doxorubicin, mitigates the drug-induced toxic actions which are reflected by the drug-induced decreases of both cellular heme and cytochrome P450 content. Sn-protoporphyrin thus provides a pharmacological means of protecting against the toxic effects of doxorubicin and other drugs which enhance heme oxygenase activity and thus decrease cellular heme and cytochrome P450 content in vivo.
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PMID:Protective effect of Sn-protoporphyrin against doxorubicin-induced perturbations of heme metabolism. 225 May 72

Effects of hexachlorobenzene (HCB) and its sulfur-containing metabolites on the heme metabolic enzymes in rat liver were investigated. A single injection of HCB caused the increase in activities of delta-aminolevulinic acid (ALA) synthetase and heme oxygenase, and contents of cytochrome P-450 and total heme. After a single injection of pentachlorothioanisol (PCTA) or pentachlorophenyl methyl sulfore (PCPSO2Me), ALA synthetase activity was enhanced. Heme oxygenase activity was increased by PCPSO2Me treatment. Cytochrome P-450 and total heme contents were increased by PCPSO2Me or 1,4-bis(methylthio)tetrachlorobenzene (MTTCB). When HCB was injected once daily for 5 weeks, a marked increase in ALA synthetase activity, a significant decrease in ALA dehydratase, almost complete inhibition of uroporphyrinogen decarboxylase activity, and an increased excretion of total porphyrin in the urine were shown. After chronic treatment with its sulfur-containing compounds, PCPSO2Me and MTTCB produced a significant increase in ALA synthetase activity. However, activities of ALA dehydratase and uroporphyrinogen decarboxylase, and excretion of total porphyrin in the urine were unaltered. At this time, the concentrations of the corresponding sulfur-containing compound and related metabolite(s) in blood, liver and kidney were nearly the same as those observed in HCB-treated rats. It is suggested that PCPSO2Me and MTTCB could induce the hepatic ALA synthetase, but, these metabolites, and also PCTA, were not able to induce the porphyria in female rats, and the induction of porphyria by HCB is not attributable to the action of its sulfur-containing compound.
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PMID:Effects of sulfur-containing metabolites of hexachlorobenzene on the heme metabolic enzymes in rat liver. 227 43

Treatment of rats with 25 or 50 mg/kg cyclosporin A for 6 days elicited vastly different responses in hepatic and renal heme and drug metabolism activities. In the liver, cytochrome P-450 concentration was decreased significantly (to 70-75% of the control). This was accompanied by a marked reduction in benzo[a]pyrene hydroxylase activity (to 20-28% of the control). Aniline hydroxylation was also decreased, but to a lesser extent (to 77% of the control). In contrast, in the kidney cytochrome P-450 concentration was significantly increased to (145-170% of the control), along with a modest decrease in benzo[a]pyrene hydroxylation activity. In this organ, the concentration of porphyrins was severely decreased (to 30% of the control). Also, the activities of delta-aminolevulinate (ALA) synthetase and ALA dehydratase, as well as that of heme oxygenase, were inhibited. It is suggested that in the kidney the inhibition of degradation, rather than an enhanced rate of synthesis of the heme molecule, contributes to the observed increase in cytochrome P-450 concentration. In the liver, the decrease in the cytochrome concentration could not be explained in terms of an alteration in the rate of heme biosynthesis or degradation. Therefore, the observed decrease in cytochrome P-450 concentration could reflect the direct inactivation of the hemoprotein or regulation of apoprotein production by cyclosporin and/or its metabolite(s). The possible relevance of the observations to cyclosporin nephrotoxicity is discussed.
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PMID:Differential effects of cyclosporin on hepatic and renal heme, cytochrome P-450 and drug metabolism. Possible role in nephrotoxicity of the drug. 249 7


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