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)

In renal failure serum bilirubin values are lower than normal. When renal failure is moderate this decrease is not due to a reduced-red-cell mass or to low levels of serum albumin. In splenic fine-needle aspirates from patients with renal failure, conditions for haem degradation were normal as indicated by normal activities of haem oxygenase and biliverdin reductase. Nor were the in vitro activities of these enzymes significantly depressed in the presence of ultrafiltrates of uraemic sera or of high concentrations of creatinine, urea or methylguanidine. The capacity of plasma from patients with renal failure to bind bilirubin was less than that of normal plasma, which at least partially explains the observed low values of serum bilirubin. There remains the possibility that in renal failure some bilirubin is removed from the plasma by a hitherto unknown route.
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PMID:Low serum bilirubin in chronic renal failure. Relation to haem metabolism. 125 56

Metalloporphyrin inhibitors of heme oxygenase may also have photosensitizing properties in vivo. To assess photoactivity in serum, the relative ability to mediate photooxidation of tryptophan or other oxidizable targets, presumably by singlet oxygen production, was measured for tin mesoporphyrin, zinc mesoporphyrin, and zinc deuteroporphyrin bisglycol in aqueous solution and when bound to human serum albumin. While tin mesoporphyrin sensitized at the greatest initial rate in aqueous solution, the zinc compounds sensitized at a greater initial rate in detergent micelles or when bound to albumin. There was minimal alteration of the tin mesoporphyrin during the time course of illumination in the Soret or visible absorption regions. The zinc compounds, however, proved to be extremely photolabile and were extensively destroyed by light; the photooxidized forms were found to be ineffective as inhibitors of heme oxygenase.
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PMID:Comparative photoactivity of tin and zinc porphyrin inhibitors of heme oxygenase: pronounced photolability of the zinc compounds. 178 Mar 55

Iodination of Sn-deuteroporphyrin (Ki = 0.185 microM) at positions C2 and C4 of the porphyrin ring results in an enhanced ability of the resulting derivative, Sn-diiododeuteroporphyrin, to inhibit (Ki = 0.069 microM) heme oxygenase activity in vitro. The potency of Sn-diiododeuteroporphyrin inhibition of bilirubin production in vivo is similar to that of Sn-protoporphyrin, but in vitro tests demonstrate that, when in solution with human serum albumin, Sn-diiododeuteroporphyrin is significantly (3-10 times, depending upon conditions) less photosensitizing than are Sn-protoporphyrin or Sn-mesoporphyrin. These findings demonstrate that halogenation of a suitable porphyrin macrocycle can substantially diminish photoactive properties of the compound whereas retaining its ability to act as a heme oxygenase inhibitor.
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PMID:Tin(Sn+4)-diiododeuteroporphyrin; an in vitro and in vivo inhibitor of heme oxygenase with substantially reduced photoactive properties. 204 22

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

A major inducible form of heme oxygenase (EC 1.14.99.3) was purified from liver microsomes of chicks pretreated with cadmium chloride. The purification involved solubilization of microsomes with Emulgen 913 and sodium cholate, followed by DEAE-Sephacel, carboxymethyl-cellulose (CM-52) and hydroxyapatite chromatography, and FPLC through Superose 6 and 12 columns operating in series. The final product gave a single band on silver-stained SDS/polyacrylamide gels (Mr = 33,000). Optimal conditions for measurement of activity of solubilized heme oxygenase were studied. In a reconstituted system containing purified heme oxygenase, NADPH-cytochrome reductase, biliverdin reductase and NADPH, the Km for free heme was 3.8 +/- 0.5 microM; for heme in the presence of bovine serum albumin (5 mol heme/3 mol albumin) the Km was 5.0 +/- 0.8 microM; and the Km for NADPH was 6.1 +/- 0.4 microM (all values mean +/- SD, n = 3). Oxygen concentration as low as 15 microM, with saturating concentrations of heme and NADPH, did not affect the reaction rate, indicating that the supply of oxygen is not involved in the physiological regulation of activity of the enzyme. The pH optimum of the reaction was 7.4; at 37 degrees C, the apparent Vmax was 580 +/- 44 nmol biliverdin.(mg protein)-1.min-1 and the molecular activity was 19.2 min-1. Biliverdin IXa was the sole biliverdin isomer formed. In the presence of purified biliverdin reductase, biliverdin was converted quantitatively to bilirubin. Addition of catalase to the reconstituted system decreased the breakdown of heme to non-biliverdin products and led to nearly stoichiometric conversion of heme to biliverdin. Activity of the enzyme in the reconstituted system was inhibited by metalloporphyrins in the following order of decreasing potency: tin mesoporphyrin greater than tin protoporphyrin greater than zinc protoporphyrin greater than manganese protoporphyrin greater than cobalt protoporphyrin. Protoporphyrin (3.3 or 6.6 microM) (and several other porphyrins) and metallic ions (100 microM) alone had little if any inhibitory effect, except for Hg2+ which inhibited by 67% at 10 microM and totally at 15 microM. Following partial cleavage, fragments of the purified enzyme were sequenced. Comparison of sequences to those derived from cDNA sequences for the major inducible rat and human heme oxygenase showed 69% and 76% similarities, respectively. The histidine residue at position 132 of rat heme oxygenase-1 and the residues (Lys128-Arg136) flanking His132 were conserved in all three enzymes, as well as in the corresponding portion of a fourth less highly similar rat enzyme, heme oxygenase-2.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Purification and characterization of heme oxygenase from chick liver. Comparison of the avian and mammalian enzymes. 215 89

The photophysical properties of Sn-protoporphyrin and two of its synthetic analogues, Sn-mesoporphyrin and Sn-diiododeuteroporphyrin, were examined. All three compounds are potent competitive inhibitors of heme oxygenase, the rate-limiting enzyme in the catabolism of heme to bilirubin, and can suppress completely or diminish significantly experimentally induced or naturally occurring forms of jaundice in animals or man. The results of these studies show that all three compounds have long-lived triplet states which are quenched by molecular oxygen both in solution and when incorporated in liposomes. However, the addition of quenching groups such as iodine to the porphyrin macrocycle results in a marked (approximately 60%) decrease in the triplet yield and a threefold decrease in the triplet lifetime. The triplet yield was shown to be independent of the excitation wavelength, and as a result, the metalloporphyrins were extremely poor photosensitizers when excited in the spectral region commonly used in phototherapy. In the presence of serum albumin, the triplet state of Sn-protoporphyrin was not quenched by oxygen. These results indicate that Sn-porphyrins can be custom designed with considerably reduced photosensitizing properties for potential clinical use as inhibitors of bilirubin production.
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PMID:Photophysical properties of Sn-porphyrins: potential clinical implications. 335 83

Sn-protoporphyrin IX (SnPP), an inhibitor of heme oxygenase and a potential therapeutic agent for neonatal hyperbilirubinemia, is bound tightly by hemopexin. The apparent dissociation constant (Kd) at pH 7.4 is 0.25 +/- 0.15 microM, but estimation of the Kd for the SnPP-hemopexin complex is hampered by the fact that at physiological pH SnPP exists as monomers and dimers, both of which are bound by hemopexin. SnPP is readily displaced from hemopexin by heme (Kd less than 1 pM). The hemopexin-SnPP interaction, like that of heme-hemopexin, is dependent on the histidine residues of hemopexin. However, as expected from the differences in the coordination chemistries of tin and iron, the stability of the histidyl-metalloporphyrin complex is lower for SnPP-hemopexin than for mesoheme-hemopexin. Nevertheless, when SnPP binds to hemopexin, certain of the ligand-induced changes in the conformation of hemopexin which increase the affinity of the protein for its receptor are produced. Binding of SnPP produces the conformational change in hemopexin which protects the hinge region of hemopexin from proteolysis, but SnPP does not produce the characteristic increase in the ellipticity of hemopexin at 231 nm that heme does. Competition experiments confirmed that human serum albumin (apparent Kd = 4 +/- 2 microM) has a significantly lower affinity for SnPP than does hemopexin. Appreciable amounts of SnPP (up to 35% in adults and 20% in neonates) would be bound by hemopexin in the circulation, and the remainder of SnPP would be associated with albumin due to the latter's high concentration in serum. Essentially no non-protein-bound SnPP is present. Importantly, SnPP-hemopexin binds to the hemopexin receptor on mouse hepatoma cells with an affinity comparable to that of heme-hemopexin and treatment of the hepatoma cells with SnPP-hemopexin causes a rapid increase in the steady state level of heme oxygenase messenger RNA. These results show that hemopexin participates in the transport of SnPP to heme oxygenase and in its regulation by SnPP.
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PMID:Interaction of hemopexin with Sn-protoporphyrin IX, an inhibitor of heme oxygenase. Role for hemopexin in hepatic uptake of Sn-protoporphyrin IX and induction of mRNA for heme oxygenase. 337 22

Sn-protoporphyrin is a strong competitive inhibitor of heme oxygenase and a potential pharmacological agent for the treatment of neonatal hyperbilirubinemia. Little is otherwise known about the biochemistry of tin porphyrins. We have investigated aspects of the chemistry of tin-protoporphyrin in aqueous solution and of its interactions with heme-binding proteins other than heme oxygenase, specifically apomyoglobin and human serum albumin. In the pH region 7-10, Soret region absorption studies of unbound Sn-protoporphyrin demonstrate a pH-dependent monomer-dimer equilibrium (KD congruent to 10(6) M-1 at pH 7) with little higher aggregation. Dissociation of the dimer is relatively slow at neutral pH, permitting interaction of protein ligands with monomeric and dimeric species to be distinguished and providing insights into kinetic mechanisms of porphyrin binding by heme-binding proteins. In the present study, the kinetics of interaction of Sn-protoporphyrin with apomyoglobin are presented as novel evidence that this binding proceeds by an induced fit mechanism. Binding of Sn-protoporphyrin to both apomyoglobin and serum albumin is unexpectedly weak. Between pH 7 and 9, the apparent affinity of Sn-protoporphyrin for apomyoglobin is less than 1/200 that of heme and, at pH 9, is also significantly less than that of protoporphyrin. The apparent affinity of Sn-protoporphyrin for human serum albumin is less than 1/1000 that of heme and 1/30 to 1/100 that of protoporphyrin. Competition studies between heme and Sn-protoporphyrin and between bilirubin and Sn-protoporphyrin indicate that Sn-protoporphyrin distributes differently among porphyrin-binding sites on serum albumin than does heme and that it is also not an effective competitor with bilirubin for bilirubin-binding sites. These results argue that Sn-protoporphyrin should not significantly alter normal mechanisms for the binding and transport of heme or of preformed bilirubin by serum albumin. From a more general perspective, the results indicate potentially unusual binding site selectivity by tin chelates; possible origins of this selectivity are discussed.
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PMID:Biochemical properties of the heme oxygenase inhibitor, Sn-protoporphyrin. Interactions with apomyoglobin and human serum albumin. 375 75

Porphyrins are transported in the serum bound to proteins and lipoproteins; the particular component(s) to which a porphyrin is bound influences its distribution in the body. In these experiments, the fractions of serum to which several metalloporphyrin inhibitors of the microsomal enzyme heme oxygenase bind were determined. Sn-mesoporphyrin and Sn-protoporphyin were associated almost entirely with serum albumin and Sn-diiododeuteroporphyrin almost completely with the lipoprotein fraction; Zn-mesoporphyrin was associated with all fractions. Serum transport proteins may be targets of photosensitization by photoactive metalloporphyrins. A decrease in the binding constant of bilirubin to Sn-mesoporphyrin-mediated photosensitized human serum albumin (HSA) was observed following illumination at 50 W/m2 in the spectral range of 520-700 nm; there were 2.0 +/- 0.2 bilirubins bound per HSA for samples illuminated < 120 min; following 180 min illumination, the stoichiometry decreased to 1.5 +/- 0.1 bilirubin per HSA. In a similar experiment with Zn-mesoporphyrin, the porphyrin was fully photooxidized to a nonphotoactive and noninhibiting product after 1 min illumination. The light reaching a porphyrin through human skin would be considerably less than that utilized under these in vitro conditions, and such effects on serum proteins, if demonstrable at all in vivo, would be expected to be far less pronounced than those measured here.
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PMID:Distribution of metalloporphyrin inhibitors of heme oxygenase among serum transport proteins. 783 84

Spectral and photodynamic properties of a porphyrin are sensitive to the environment in which it is localized. By comparison of absorption maxima of porphyrins bound to micelles, proteins or artificial membranes with peak wavelengths in homogeneous solutions of known dielectric constant, the relative polarity of the microenvironment surrounding a porphyrin can be estimated. We have focused our examination on the ability of two synthetic metalloporphyrin inhibitors of heme oxygenase, Sn(IV)-mesoporphyrin (SnMP) and Zn(II)-mesoporphyrin (ZnMP), to partition into charged and uncharged detergent micelles and liposomes. SnMP and ZnMP are intercalated into micelles with cationic surface charges but only ZnMP into nonionic micelles, suggesting that the ionic character of the two anionic axial ligands of SnMP, as well as that of the ionized carboxylic acids of both porphyrins, is a predominant force in the interactions of these compounds. Absorbance shifts of SnMP and ZnMP bound to serum albumin suggest that both porphyrins are localized within an environment with polarity similar to that of ethanol. Spectral changes upon incubation of ZnMP into liposomes (with or without surface charges) indicate that the porphyrin is incorporated into the polar region of the bilayer, i.e. at the border between hydrophilic headgroups and hydrophobic lipids. Illumination of ZnMP within the liposomal membrane resulted in a rapid rate of oxygen uptake, consistent with lipid peroxidation occurring within the bilayer.
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PMID:Incorporation of metalloporphyrin inhibitors of heme oxygenase into micelles and liposomes. 783 85


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