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)

Zinc protoporphyrin IX (ZnPP) has been shown to inhibit heme oxygenase (HO) activity effectively in vivo and has potential in the treatment of neonatal jaundice. Because this is a transitional or temporary condition lasting only several days, an effective chemopreventive agent with a relatively short duration of action would be desirable for the treatment of severe neonatal jaundice. To determine the effective duration of action of ZnPP, we administered either 40 nmol/g of body weight ZnPP or 5 microL/g body weight diluent intraperitoneally to neonatal rats 24-36 h after birth. Between 0 and 21 d after ZnPP dosing, the duration of action was investigated through measurements of serum bilirubin and hepatic and splenic HO inhibition, which were correlated to measurements of ZnPP distribution. Significant (p < 0.05) hepatic HO inhibition, ranging from 27 to 51%, was observed in the liver between 1 and 4 d after dosing, concurrent with a 23-28% reduction in serum bilirubin levels, and was associated with ZnPP tissue concentrations of 27-38 nmol/g. Splenic HO was not inhibited measurably by the much lower concentrations of ZnPP found in the spleen (2.8-20.1 nmol/g) between 0 and 21 d after dosing. Furthermore, HO isoform 1 (HO-1) induction was apparently not a confounding factor in the duration of action of ZnPP, because the modest increases in HO-1 protein levels were not sustained longer than 24 h after ZnPP administration. Our findings demonstrated that the duration of action of ZnPP in neonatal rats is less than 1 wk. The reduction in serum bilirubin levels, the short duration of action and minimal confounding effects suggest that ZnPP may be an effective chemopreventive agent for the treatment of severe neonatal jaundice.
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PMID:Duration of action and tissue distribution of zinc protoporphyrin in neonatal rats. 872 67

Synthetic metalloporphyrin derivatives of heme have been identified as competitive inhibitors of heme oxygenase, the rate-limiting enzyme in the heme degradation pathway that produces equimolar quantities of carbon monoxide, biliverdin, and bilirubin. Therefore, administration of metalloporphyrin has been proposed as one means to prevent excessive hyperbilirubinemia in human neonates. Tin proto- and meso-porphyrin have been studied for the suppression of neonatal jaundice. However, these compounds are also photosensitizers. This property may limit the clinical use of these compounds, particularly in infants being exposed simultaneously to phototherapy. Via measurements of carbon monoxide, we have studied the photooxidative, metabolic, and inhibitory characteristics of metalloporphyrins that have not yet been studied for this purpose: deuteroporphyrin bisglycol (DBG), iron deuteroporphyrin bisglycol (FeBG), tin deuteroporphyrin bisglycol (SnBG),tin deuteroporphyrin (SnDP), chromium deuteroporphyrin (CrDP), and zinc deuteroporphyrin (ZnDP). Of the six compounds, SnDP, SnBG, and DBG were significantly photoreactive in vitro. Furthermore, in vitro measurements of brain, liver, and spleen heme oxygenase activity inhibition indicated that, of the nonphotoreactive compounds, CrDP and ZnDP were the most potent inhibitors. Only FeBG served as a substrate for the heme oxygenase reaction. The concentration for 50% inhibition with the three tissues ranged from 0.6 to 1.3 microM for CrDP and from 11.0 to 13.5 microM for ZnDP. When 25 mumol CrDP and 50 mumol ZnDP per kilogram body weight were administered to rats given a heme load of 30 mumol/kg body weight, the total body carbon monoxide excretion due to the administered heme load was reduced by 46 and 32%, respectively, at t = 7.5 h, when the experiment was terminated in order to measure heme oxygenase activity. Brain heme oxygenase activity was not affected by the metalloporphyrin treatment. However, both CrDP and ZnDP inhibited liver tissue heme oxygenase activity to 5 and 20%, respectively, whereas only CrDP inhibited spleen tissue heme oxygenase, to 7% of untreated control. Thus, CrDP appears to be the most attractive of the six compounds and deserves further study.
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PMID:Characterization of porphyrin heme oxygenase inhibitors. 877 7

The workshop covered three major areas: Unconjugated bilirubin (UCB) chemistry and physical chemistry; UCB transport and intracellular trafficking; and evaluation and therapy of neonatal and congenital hyperbilirubinemias. Findings of studies in the chemistry and physical chemistry area were as follows. (1) Nuclear magnetic resonance (NMR) studies of highly enriched 13COOH mesobilirubin in water-dimethyl sulfoxide systems indicated that the pKa values of the carboxyl groups are 4.2 and 4.9, respectively. This finding differs from some reports that suggest that the two pKa values in aqueous systems are near or above pH 7.0. (2) Contrasting views of the hydrophobic interactions of UCB with bile salts were presented: one suggested that multiple bile salt monomers bind to one UCB molecule; the other suggested that UCB binds to the nonpolar surface of helical bile salt micelles. (3) Structures were proposed for the varied calcium and copper bilirubinate salts formed at various pH values and cation/UCB ratios. (4) Studies of binding of UCB to human serum albumin (HSA) showed marked diminution of UCB-binding affinity as albumin and chloride concentrations increased. (5) A unique UCB derivative, bilirubin-C10-sulfonic acid, was identified as the major bile pigment in bullfrog bile. (6) New methods were presented for removal of impurities from preparations of bile salts and UCB. Findings of studies in the transport area were as follows. (1) Four putative basolateral and two putative canalicular hepatocytic transporters of UCB and related organic anions were described. Special emphasis was given to the adenosine triphosphate (ATP)-dependent canalicular multi-specific organic anion transporter that is defective in three strains of mutant rats with congenital conjugated hyperbilirubinemia. (2) The roles of the classical and newer molecular biological approaches to identification of these transporters were contrasted, and their limitations were discussed. (3) The relative roles of the multiple carriers in UCB transport under different conditions and substrate concentrations were discussed. (4) Cytosolic UCB-binding proteins (e.g., ligandin) were shown to promote transcellular movement of UCB by solubilizing and transporting the pigment in the aqueous phase while limiting binding of UCB to the relatively immobile membranes of cell organelles. (5) Mechanisms were presented for translocation of UDP-glucuronic acid (UDPGA) into the lumenal location of UDPGA transferase in the endoplasmic reticulum, as well as the enhancement of this process by N-acetyl-glucosamine. Studies in the neonatal and congenital jaundice area were as follows. (1) Criteria were reviewed for initiating treatment of neonatal jaundice, emphasizing the primacy of serum bilirubin levels, gestational age, and hemolysis as risk factors for kernicterus. (2) New methods were presented for frequent, automated monitoring of serum bilirubin levels and breath CO levels as an index of rates of formation of UCB from heme. (3) The current status and limitations of new approaches to treatment of severe unconjugated hyperbilirubinemia were discussed: hepatocyte transplantation and gene therapy, still in the stage of development in animal models, have provided only partial and temporary relief of hyperbilirubinemia; extracorporeal liver assist devices have had some success in initial human studies; and inhibition of heme oxygenase (HO) with metalloporphyrins, especially tin mesoporphyrin, which markedly decreases bilirubin production for prolonged periods, is a new alternative to phototherapy. (4) The ontogeny of the two HO isozymes was contrasted in the liver, spleen, kidney, and lung.
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PMID:New concepts in bilirubin and jaundice: report of the Third International Bilirubin Workshop, April 6-8, 1995, Trieste, Italy. 890 13

Neonatal jaundice continues to be a common problem. Kernicterus, although rare, continues to be a very real concern in both full-term and preterm infants. The diagnosis of kernicterus requires not only bilirubin staining in a characteristic pattern in the brain but also neuronal damage. With careful pathologic evaluation, kernicterus should be distinguishable from the brain damage associated with asphyxia and hypoxia. Early hospital discharge is a risk factor for the development of kernicterus. Combining the use of traditional phototherapy from above and a fiberoptic blanket from below has improved the effectiveness of phototherapy. Clinical trials with SnMP as an inhibitor of heme oxygenase appear encouraging; no adverse effects were noted, except for mild, occasional photosensitization manifest by erythema in babies receiving phototherapy. One theoretical toxicity of inhibitors of heme oxygenase involves the recent observation that carbon monoxide (CO) is a neurotransmitter in certain regions of the brain, possibly comparable to nitric oxide (NO), and the consequences of such inhibition are unknown. More research is needed to improve our understanding about the entry of bilirubin into the brain, the predilection of bilirubin for certain brain regions, and the cytotoxicity of bilirubin. In the United States, there is currently no generally accepted method to predict hyperbilirubinemia or kernicterus. Brain stem auditory evoked responses and MRI can both be used effectively to monitor the effects of severe hyperbilirubinemia.
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PMID:Bilirubin metabolism and kernicterus. 926 71

Bilirubin, a product of haemoglobin metabolism, has been suggested to damage neurons by increasing activation of N-methyl-D-aspartate (NMDA) receptors when it reaches high levels in the blood [15,19], as occurs in neonatal jaundice [7]. Bilirubin is also generated in the brain following synthesis of the messenger carbon monoxide (CO) by haem oxygenase, and haem oxygenase is upregulated in Alzheimer's disease [23]. We examined the effect of bilirubin on currents generated by NMDA and alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) receptors in hippocampal pyramidal cells, and on glutamate transporter currents in retinal glial cells. Bilirubin did not modulate either receptor-gated currents or transporter currents. These data show the negative, but important result that bilirubin does not induce neuronal death by acting directly on NMDA or AMPA receptors, nor indirectly by blocking glutamate uptake and raising the extracellular concentration of glutamate.
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PMID:Bilirubin does not modulate ionotropic glutamate receptors or glutamate transporters. 1101 Oct

Jaundice is a common cause for diagnostic works-up and therapeutic intervention in neonates. This is motivated by the risk for severe neurological sequelae (kernicterus). The mainstays of treatment for the past decades have been exchange transfusion and phototherapy. Exchange transfusion is now becoming rare due to immune prophylaxis in Rhesus-negative women, and treatment of sensitised infants with intravenous immunoglobulin. Several different pharmacological approaches have been studied as far as the treatment of neonatal jaundice. Of these, the focus of attention in recent years has been on the haem oxygenase inhibitors (metal meso- and protoporphyrins). These are effective inhibitors of bilirubin production and have been shown to significantly reduce peak serum bilirubin levels in several clinical trials, both when used prophylactically and therapeutically. However, questions remain regarding long-term safety, as well as the advisability of whole-scale inhibition of bilirubin production. Nevertheless, in selected infants with a high risk of severe jaundice, the use of haem oxygenase inhibitors may be acceptable. Pharmacotherapy in jaundiced infants is fraught with risks, as many drugs may increase the entry of bilirubin into the brain and presumably, the risk for neurotoxicity. Both the displacement of bilirubin from its albumin binding and interference with the function of phosphoglycoprotein in the blood-brain barrier are documented mechanisms in this respect.
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PMID:Recent advances in the pharmacotherapy for hyperbilirubinaemia in the neonate. 1459 47

Some metalloporphyrins (Mps) inhibit heme oxygenase (HO), the rate-limiting enzyme in the production of bilirubin, and are potential compounds for the treatment of neonatal jaundice. We studied the safety and efficacy of Mps following oral administration. Adult HO-1-luc reporter mice were administered 30 micromol/kg body weight of tin mesoporphyrin (SnMP), zinc bis glycol deuteroporphyrin (ZnBG), or zinc protoporphyrin (ZnPP), or vehicle by oral gavage. Bilirubin production was measured as total body carbon monoxide (CO) excretion (VeCO). HO activity was quantitated via CO measurements by gas chromatography. HO-1 protein was determined by Western blot. HO-1 transcription levels were assessed by in vivo bioluminescence imaging. A significant 28% decrease in bilirubin production occurred within 3 h of SnMP treatment and persisted beyond 48 h. Bilirubin production decreased 15% and 9% by 3 h after administration of ZnBG and ZnPP, respectively, but returned to baseline within 48 h. Maximal inhibition of liver, spleen, and intestine HO activity was seen at 3 h with inhibitory effects decreasing in the order: SnMP > or = ZnBG > or = ZnPP. After SnMP treatment, HO-1 transcription increased 5.7-fold after 24 h. Furthermore, liver and spleen HO-1 protein significantly increased 3.7- and 2.0-fold, respectively, after 24 h. HO-1 transcription and protein were not affected in ZnBG- or ZnPP-treated mice. We conclude that the three Mps are absorbed at different rates in the mouse and affect bilirubin production and HO-1 expression in a tissue- and time-dependent manner.
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PMID:Systemic effects of orally-administered zinc and tin (IV) metalloporphyrins on heme oxygenase expression in mice. 1662 79

Inhibition of heme oxygenase (HO), the rate-limiting enzyme in heme catabolism, may be an ideal strategy for preventing neonatal jaundice. Although natural and synthetic heme analogs, called metalloporphyrins (Mps), have been extensively investigated for this purpose, some Mps are phototoxic, affect the activity of other enzymes, or induce HO-1 transcription-properties that may limit their clinical use. Another class of compounds, imidazole-dioxolanes, has been shown to selectively inhibit the inducible isozyme HO-1. Therefore, we investigated the efficacy of azalanstat (AZA), an imidazole-dioxolane, towards inhibiting HO activity in 7-day-old mice. We found that a single dose of AZA at 500 micromol.kg(-1) body mass (BM) administered i.p. significantly inhibited HO activity and reduced in vivo bilirubin production. In the spleen, HO inhibition (>50%) was observed within 0.25-3 h after administration. After 24 h, however, spleen HO activity, HO-1 protein, and HO-1 mRNA levels significantly increased 1.2-, 2.4-, and 4.0-fold, respectively. We conclude that AZA effectively inhibits in vivo HO activity only at a high dose and that it also induces spleen HO-1 gene transcription. Therefore, other imidazole-dioxolanes should be evaluated to determine whether they are more potent than AZA for use in treating neonatal jaundice.
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PMID:Inhibition of heme oxygenase activity in newborn mice by azalanstat. 1884 Nov 69

In order to obtain a better molecular understanding of inhibitory role of tin metal in the verdoheme ring opening process, hydrolysis of three possibly six, five, and four coordinate verdoheme complexes of tin(IV) and (II) have been studied using DFT method. The results of calculations indicate that, in excellent accord with experimental reports, hydrolysis of different possibly coordinated tin(IV) and (II) verdohemes does not lead to the opening of the macrocycle. Contrary to iron and zinc verdohemes, in five and four coordinate verdoheme complexes of tin(IV) and (II), formation of open ring helical complexes of tin are unfavorable both thermodynamically and kinetically. In these pathways, coordination of hydroxide nucleophile to tin metal due to the highly charged, exclusive oxophilicity nature of the Sn center, and high affinity of Sn to increase coordination state are proposed responsible as inhibiting roles of tin via the ring opening. While, in saturated six coordinate tin(IV) and (II) verdoheme complexes the ring opening of tin verdohemes is possible thermodynamically, but it is not predicted to occur from a kinetics point of view. In the six coordinate pathway, tin plays no coordination role and direct addition of hydroxide nucleophile to the positive oxo-carbon centers and formation of closed ring hydroxy compounds is proposed for preventing the verdoheme ring opening. These key points and findings have been corroborated by the results obtained from atomic charge analysis, geometrical parameters, and molecular orbital calculations. In addition, the results of inhibiting ring opening reaction of tin verdoheme complexes could support the great interest of tin porphyrin analogues as pharmacologic means of chemoprevention of neonatal jaundice by the competitive inhibitory action of tin porphyrins on heme oxygenase.
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PMID:Theoretical investigations on the hydrolysis pathway of tin verdoheme complexes: elucidation of tin's ring opening inhibition role. 1937 97

Neonatal jaundice in the first week of life is a common problem in newborns. It is due to an imbalance of bilirubin production and its elimination, which can lead to significantly elevated levels of circulating bilirubin or hyperbilirubinemia. Use of phototherapy and/or exchange transfusion are the current modes for treating neonatal hyperbilirubinemia and preventing any neurologic damage. These strategies, however, only remove bilirubin that has already been formed. Preventing the production of excess bilirubin may be a more logical approach. Synthetic heme analogs, metalloporphyrins, are competitive inhibitors of heme oxygenase, the rate-limiting enzyme in bilirubin production, and their use has been proposed as an attractive alternative strategy for preventing or treating severe hyperbilirubinemia.
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PMID:Metalloporphyrins in the management of neonatal hyperbilirubinemia. 2000 67


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