Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:1.14.99.3 (heme oxygenase)
 4,196 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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

The protective effect of SKF 525-A on the suppression of cytochrome P-450 content and monooxygenase activities by treatment with CoCl2 and polyriboinosinic acid-polyribocytidylic acid [poly(I.C] was compared as a part of studies of suppression of drug metabolizing enzymes by interferon inducers. Induction of heme oxygenase activity by CoCl2 and poly (I.C) was not altered by simultaneous treatment with SKF 525-A. Depression of cytochrome P-450 content and benzphetamine N-demethylase activity by treatment with CoCl2 was prevented by co-treatment with SKF 525-A. This effect was explained by the prevention of release of heme from cytochrome P-450 by forming metabolic intermediate complexes with metabolites of SKF 525-A. On the other hand, poly(I.C) significantly suppressed P-450 content and benzphetamine N-demethylase and benzo [a] pyrene hydroxylase activities, even under simultaneous treatment with SKF 525-A. This inhibition by poly (I.C) was accompanied by weak staining of proteins corresponding to cytochrome P-450 in SDS gel electrophoresis. In addition, the activity of non-heme enzyme, 4-hydroxybiphenyl glucuronyltransferase, was suppressed by treatment with poly (I.C) but not by CoCl2-treatment. These findings strongly suggested that, unlike CoCl2, poly (I.C) suppressed cytochrome P-450 content and monooxygenase activities due to decreased synthesis or increased degradation of the apoprotein of cytochrome P-450 with slight contribution of the induced heme oxygenase.
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PMID:Effect of co-administration of interferon inducer, polyriboinosinic acid-polyribocytidylic acid, with SKF 525-A on hepatic drug metabolizing enzymes of rats. 309 97

The effects of tricyclohexyltin hydroxide on the induction of cytochrome P-450 in liver by phenobarbital, 3-methylcholanthrene and beta-naphthoflavone were studied. A single dose of the organotin (15 mg/kg body wt) prevented the full extent of phenobarbital induction of cytochrome P-450 from occurring; this was the case whether tricyclohexyltin was given 48 hr preceeding a single injection of phenobarbital, or administered simultaneously with the first of three daily doses of the drug. Elevation of hepatic heme oxygenase (EC 1.14.99.3) activity accompanied these changes in cytochrome P-450, but the induction of this enzyme was not affected by phenobarbital treatment. The induction of cytochrome P-448 by 3-methylcholanthrene and beta-naphthoflavone was not affected to the same extent by a single injection of tricyclohexyltin, while heme oxygenase induction was less pronounced when these cytochrome P-448 inducers were given together with the organotin. The changes in cytochrome P-450 content and in its functional activity resulting from the various treatments were further examined by sodium dodecyl sulfate (SDS)-polyacrylamide gel electrophoresis of the microsomal fractions. The electrophoretic profiles illustrate clearly that the apoprotein moieties of the various cytochrome P-450 subspecies are affected to a considerable extent by treatment with tricyclohexyltin hydroxide alone, and staining in these bands was noticeably reduced even when phenobarbital was administered together with the organotin. In contrast, tricyclohexyltin failed to decreased the 3-methylcholanthrene- or beta-naphthoflavone-induced cytochrome P-450 subspecies. These data suggest that significant metabolic interactions can occur from exposure to a combination of environmental chemicals and drugs resulting in an altered metabolism of heme and cytochrome P-450.
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PMID:Altered induction response of hepatic cytochrome P-450 to phenobarbital, 3-methylcholanthrene, and beta-naphthoflavone in organotin-treated animals. 398 2

The treatment of rats with cis-platinum for 7 days caused a profound, and seemingly selective, decrease (70-80%) in the microsomal cytochrome P-450 levels in the testis. This decrease was accompanied by marked reductions (70-80%) in steroid 17 alpha-hydroxylase activity and in plasma testosterone concentration. The treatment of rats with human chorionic gonadotropin partially restored the cytochrome P-450 concentration and 17 alpha-hydroxylase activity and permitted the plasma testosterone level to approach control values. The effect of cis-platinum on the testicular cytochrome P-450 appeared unrelated to deficiencies in heme metabolic processes, in so far that neither was the activity of delta-aminolevulinate synthetase decreased, nor was that of heme oxygenase increased. These enzymes are rate-limiting in heme biosynthesis and degradation pathways, respectively. Also, the activities of uroporphyrinogen I synthetase, delta-aminolevulinate dehydratase, and ferrochelatase and the concentration of total porphyrins in the testis remained unchanged. The sodium dodecyl sulfate-gel electrophoresis of the microsomal preparation did not reveal a diminished level of apocytochrome; however, in this preparation, heme could not be detected in molecular weight regions corresponding to cytochrome P-450. The microsomal cytochrome b5 and the mitochondrial heme concentrations were not decreased in cis-platinum-treated rats. It is suggested that the mechanism of depletive action of cis-platinum on microsomal cytochrome P-450 involves an impairment of the effective assembly of heme and apoprotein moieties. It is further suggested that the anterior pituitary hormones control the factor(s) involved in this assembly, a process which is interrupted by cis-platinum.
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PMID:Inhibition of testicular cytochrome P-450-dependent steroid biosynthesis by cis-platinum. Reversal by human chorionic gonadotropin. 403 24

In the rat testis, 7 days after hypophysectomy, the microsomal content of cytochrome P-450 decreased to a negligible level. The sodium dodecyl sulfate gel electrophoresis of the microsomal preparation did not reveal a decrease in apocytochrome P-450; however, in this preparation, heme was undetectable. The latter did not reflect decreases in the activities of the heme biosynthesis enzymes. Also, an increase in heme oxygenase activity did not appear responsible for the suppression of the cytochrome levels. The cellular basis for the depression of the cytochrome was explored by measuring the incorporation of [14C]delta-aminolevulinate into the testicular microsomal and mitochondrial hemoproteins, and determining the relative affinity of microsomal heme for the endoplasmic reticulum membranes. In comparison with the sham-operated animals, in hypophysectomized rats, the specific 14C activity of heme in mitochondrial fraction was not decreased; however, that of the microsomal fraction was markedly reduced. The latter appeared to reflect a lowered binding affinity of the apoprotein moiety of cytochrome P-450 for heme. The treatment of hypophysectomized rats with human chorionic gonadotropin partially restored the normal level of the cytochrome. It is suggested that the anterior pituitary hormones control the level of cytochrome P-450 in the testis through factors which do not involve the production of heme; rather, the control appears to involve the processes of assembly of the hemoprotein and the association of the heme molecule with the apoprotein.
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PMID:Dissociation of heme metabolic activities from the microsomal cytochrome P-450 turnover in testis of hypophysectomized rats. 674 60

Cyanobacteria, red algae, and cryptophytes contain phycobiliproteins which function as photosynthetic light-harvesting pigments. The chromophores of phycobiliproteins are phycobilins, open-chain tetrapyrroles that are synthesized from protoheme. The first step of phycobilin formation is the conversion of protoheme to biliverdin IX alpha in a reaction that is catalyzed by heme oxygenase. In the unicellular red alga, Cyanidium caldarium, light is required for the accumulation of phycobiliproteins. It has been reported previously that the synthesis of the apoprotein components of allophycocyanin and phycocyanin is induced by light in C. caldarium, that the phycobilin precursors, delta-aminolevulinic acid (ALA), protoporphyrin IX, and protoheme can substitute for light, and that the regulation is exerted at the level of mRNA synthesis. We have determined that a key enzyme of phycobilin formation is induced by light in C. caldarium. Extractable heme oxygenase activity is low in dark-grown cells, and it increases approximately 6-fold during the first 24 h after the cells are illuminated. After 24 h, the activity decreases to a level approximately equal to the initial activity. Heme oxygenase is induced in unilluminated cells by administration of ALA. D-Glucose, which is known to inhibit phycocyanin accumulation in C. caldarium, inhibits the induction of heme oxygenase by light or ALA. Induction of heme oxygenase by light or ALA is blocked by cycloheximide, an inhibitor of cytoplasmic protein synthesis, but not by chloramphenicol, an inhibitor of chloroplast protein synthesis. Rifampicin, an inhibitor of algal chloroplast RNA synthesis, and gabaculine, a competitive inhibitor of ALA biosynthesis, block the induction of heme oxygenase by light but not by ALA. These results indicate that heme oxygenase in C. caldarium is induced by phycobilin precursors. The induction by light and the repression of the induction by D-glucose are probably indirect effects mediated by the effects of light and D-glucose on phycobilin precursor formation. The results also indicate that heme oxygenase is encoded by a nuclear gene and is synthesized on cytoplasmic ribosomes.
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PMID:Regulation of heme oxygenase activity in Cyanidium caldarium by light, glucose, and phycobilin precursors. 814 49

The differential induction of hepatic cytochrome P-450 (P450) was studied in Eisai-hyperbilirubinuria rats (EHBR/Eis). This rat is a mutant that has as high a concentration of bilirubin in the urine as in the plasma. A single administration of trans-stilbene oxide (TSO, 2 mmol/kg), a phenobarbital (PB)-type P450 inducer, did not increase total P450, the CYP2B1/2 or the CYP2C6 in EHBR/Eis liver. TSO was able to induce delta-aminolevulinic acid synthetase and heme oxygenase, rate-limiting enzymes in heme biosynthesis and degradation, respectively, in both EHBR/Eis and Sprague-Dawley rat (SDR), the strain from which EHBR/Eis is derived. TSO also produced similar effects on glutathione depletion and on the activities of other drug-metabolizing enzymes in both strains. A 23-fold increase in CYP2B1/2 mRNA in the SDR liver was observed 24 hr after TSO treatment. In the EHBR/Eis strain, however, TSO increased CYP2B1/2 mRNA only 2-fold. In addition, repeated injection of TSO failed to induce P450 isozymes, CYP2B1/2, CYP2C6 or CYP3A2 in EHBR/Eis. On the other hand, there was essentially no difference in the induced levels of CYP1A1/2 apoprotein and mRNA between twins of SDR and EHBR/Eis livers treated with 3-methylcholanthrene or 1-benzylimidazole. The increased levels of both CYP2B1/2 apoprotein and mRNA from EHBR/Eis liver treated with TSO and 1-benzylimidazole were much smaller (2.5- and 5-fold increases, respectively) than from the SDR liver (17.5- and 15-fold increases, respectively). Although PB expressed CYP2B1/2 apoprotein and mRNA to a similar extent in both homozygous and heterozygous EHBR/Eis livers, CYP3A2 and CYP2C6 were less responsive to PB in homozygous EHBR/Eis. Repeated treatment with TSO induced these isozymes in heterozygote but not in homozygote. These findings suggest that the suppressed expression of PB-inducible P450 isozyme genes in the EHBR/Eis liver may be a general phenomenon associated with PB-type inducers. Therefore, EHBR/Eis may be experimentally useful for studying the mechanism of P450 induction by PB and PB-type inducers.
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PMID:Suppressed expression of phenobarbital-inducible hepatic cytochrome P-450s in Eisai-hyperbilirubinuria rats (EHBR/Eis). 866 38

Heme metabolism normally involves enzymatic conversion to biliverdin and subsequently to bilirubin, catalyzed by heme oxygenase and biliverdin reductase, respectively. We examined the ability of exogenously added hemin, biliverdin, or bilirubin to regulate Cyp1a1, an enzyme that may be active in bilirubin elimination. A substantial dose-dependent increase in Cyp1a1 mRNA occurred after treatment of Hepa 1c1c7 cells with either of the three compounds. This increase was readily apparent 1 hr after treatment with biliverdin or bilirubin but required >/=2 hr with hemin. Treatment of Hepa 1c1c7 cells with these compounds also caused a dose-dependent increase in Cyp1a1-dependent 7-ethoxyresorufin-O-deethylase (EROD) activity. Of the three compounds, bilirubin produced the greatest maximal increase in Cyp1a1 mRNA and EROD (5.5-, 10.5-, and 15-fold for 100 microM hemin, biliverdin, and bilirubin, respectively) activity. The RNA polymerase inhibitor actinomycin D completely blocked Cyp1a1 induction by these compounds, indicating a requirement for de novo RNA synthesis via transcriptional activation. The protein synthesis inhibitor cycloheximide did not affect Cyp1a1 mRNA induction, indicating a lack of requirement for labile protein factors. In contrast, EROD induction by hemin, biliverdin, or bilirubin was completely blocked by cycloheximide treatment, indicating that the increase in enzyme activity is dependent on increased Cyp1a1 apoprotein synthesis. Aryl hydrocarbon receptor (AHR)- and AHR nuclear translocator-deficient mutant Hepa 1c1c7 cells did not exhibit increased Cyp1a1 mRNA or EROD activity after treatment with these compounds, indicating the requirement for a functional AHR for this response. Consistent with this, hemin, biliverdin, and bilirubin were able to induce expression of the dioxin-response element/luciferase reporter plasmid pGudLuc1.1 after transient transfection into wild-type Hepa 1c1c7 cells. Gel retardation assays demonstrated that bilirubin, but not hemin or biliverdin, was able to transform the AHR to a form capable of specifically binding to a 32P-labeled oligonucleotide containing a dioxin-response element sequence. These data indicate that bilirubin induces Cyp1a1 gene transcription through direct interaction with the AHR. In contrast, hemin and biliverdin seem to induce Cyp1a1 indirectly by serving as precursors to the endogenous formation of bilirubin via normal heme metabolism pathways. This is the first direct demonstration that the endogenous heme metabolite bilirubin can directly regulate Cyp1a1 gene expression and enzymatic activity in an AHR-dependent manner.
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PMID:Aryl hydrocarbon receptor-dependent induction of cyp1a1 by bilirubin in mouse hepatoma hepa 1c1c7 cells. 938 21

The effect of recombinant human interleukin-1beta (IL-1beta) on the modulation of hepatic cytochrome P450 (P450) was investigated by in vivo subcutaneous dosing studies in male Sprague-Dawley rats. To assess the effect of IL-1beta on heme metabolism, we determined the delta-aminolevulinic acid synthetase (delta-ALAS) and heme oxygenase activities in the liver. IL-1beta suppressed the microsomal total P450 and heme contents and delta-ALAS activity in the liver. In contrast, microsomal heme oxygenase activity was significantly increased by the IL-1beta treatments. Western blot analysis and marker enzyme activities for individual P450 isoforms demonstrated that IL-1beta suppressed CYP2C6, 2C13, 2E1, and 3A2, whereas CYP2A, 2B1/2, 2C11, and 4A1 were not influenced by the treatments. IL-1beta inhibited both allylisopropylamide- and phenobarbital-inducible delta-ALAS activities in the liver. These results indicate that IL-1beta has differential effects on the constitutive P450, and also on delta-ALAS and heme oxygenase activities in rat liver. Thus, the modulation of hepatic P450 by IL-1beta is complex, and IL-1beta may be involved in the regulation of both apoprotein synthesis for each P450 isoform and the heme pools in the liver.
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PMID:Role of interleukin-1beta in the modulations of cytochrome P450 and heme metabolism in rat liver. 1043 60

NADPH-P450 oxidoreductase (CPR) is essential for the activity of cytochrome P450 (P450). Previous studies demonstrated that CPR regulates the levels of various P450 isoforms in vitro. We investigated the mechanistic basis for this regulation. By transfection of Chinese hamster ovary DUKXB11 cells we obtained the cell line DUKX/2D6, which expressed human CYP2D6, a P450 isoform. Subsequently, DUKX/2D6 cells were transfected with human CPR cDNA to generate the cell line DUKX/2D6/CPR-3. Expression of recombinant CPR decreased the level of spectrally detectable CYP2D6 holoprotein in DUKX/2D6/CPR-3 cells by 70%, whereas the level of immunodetectable apoprotein remained unchanged. Addition of the radical scavenger DMSO increased levels of CYP2D6 holoenzyme in DUKX/2D6/CPR-3 cells but not in DUKX/2D6 cells. A similar effect was noted when cells were grown in the presence of hemin. Importantly, combined treatment with DMSO and hemin increased levels of CYP2D6 holoenzyme in DUKX/2D6/CPR-3 but not in DUKX/2D6 cells even further than either treatment alone. None of these treatments affected the level of immunodetectable CYP2D6. This demonstrates that expression of CPR increases production of damaging radicals but also that CPR may alter haem homoeostasis. In agreement with this, the activity of haem oxygenase, a rate-limiting enzyme in haem metabolism, was compared with that in DUKX/DHFR control cells (expressing dihydrofolate reductase), and was 3-fold higher in DUKX/2D6/CPR-3 but similar in DUKX/2D6 cells. Furthermore, treatment of cells with sodium arsenite increased levels of haem oxygenase concomitant with a marked decrease of spectrally detectable CYP2D6 and a rise in levels of ferritin, which sequesters free iron released from the destruction of haem. These data demonstrate that CPR regulates P450 activity by supplying electrons and also by altering P450 levels via radical-and haem oxygenase-mediated pathways.
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PMID:Human NADPH-P450 oxidoreductase modulates the level of cytochrome P450 CYP2D6 holoprotein via haem oxygenase-dependent and -independent pathways. 1136 92


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