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)

Sn (tin)-mesoporphyrin (Sn-protoporphyrin in which the vinyl groups at C2 and C4 have been reduced to ethyl groups) when incubated with rat splenic microsomal heme oxygenase proved to be a potent competitive inhibitor of enzyme activity in vitro, with a Ki of 0.014 microM. Sn-mesoporphyrin (1 mumol/kg body wt) also inhibited hepatic, renal, and splenic heme oxygenase activity in vivo in adult animals for extended periods of time. Sn-mesoporphyrin (1 mumol/kg body wt) prevented the transient increase in serum bilirubin 24 h after birth in the rat neonate and substantially reduced the levels of serum bilirubin in ALA (delta-aminolevulinic acid) induced hyperbilirubinemia in the 7-day-old suckling neonate. Tissue heme oxygenase activity was decreased in both animal models of hyperbilirubinemia. Sn-mesoporphyrin administration led to a prolonged increase in the heme saturation of hepatic tryptophan pyrrolase indicating an increase in the "heme pool" related to tryptophan pyrrolase and the compound also suppressed chemically induced hepatic porphyria. The administration of Sn-mesoporphyrin to bile duct-cannulated rats was followed by a prompt and sustained decrease in bilirubin output in bile. In addition the excretion of heme in bile was enhanced in these animals. These studies indicate that Sn-mesoporphyrin, like Sn-protoporphyrin, decreases serum bilirubin by inhibiting the production of bilirubin in vivo and its mode of action is through a sustained competitive inhibition of heme oxygenase. However, when a direct comparison of Sn-protoporphyrin and Sn-mesoporphyrin was made, these studies clearly established that the reduction of the C2 and C4 vinyl groups of the porphyrin macrocycle to ethyl groups increases the effectiveness of the Sn-mesoporphyrin derivative 10-fold or more as compared with Sn-protoporphyrin in inhibiting heme catabolism in the animal model systems examined. Thus alterations in the side chain substituents as well as of the central metal atom can influence in a significant manner the potency of the resultant synthetic heme analog as an agent capable of inhibiting heme degradation in vivo.
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PMID:Reduction of the C2 and C4 vinyl groups of Sn-protoporphyrin to form Sn-mesoporphyrin markedly enhances the ability of the metalloporphyrin to inhibit in vivo heme catabolism. 359 68

The magnitude and duration of drug action is determined partially by the activity of the drug metabolizing enzyme systems in the liver. The pharmacological effectiveness of many drugs is altered during the aging process. In this study, the regulation of heme metabolism and hemoprotein content was examined in livers of aged female rats. The activities of hexobarbital hydroxylase and aniline hydroxylase, indicators of mono-oxygenase function, were decreased in aged rats by 31% and 24%, respectively, as compared to values in young rats. This was accompanied by a proportional decrease in the level of cytochrome P-450 (26%). Additionally, the activity of delta-aminolevulinic acid synthetase (ALA-S), the rate-limiting enzyme in heme synthesis, and the microsomal concentration of heme were also decreased by 33% and 26%, respectively, in these animals. In contrast, the basal activity of microsomal heme oxygenase (MHO), the rate-limiting enzyme in heme degradation, and the percent heme saturation of tryptophan pyrrolase (TPO), a sensitive indicator of changes in the availability of heme in the "regulatory" heme pool, were increased by (87%) and (31%), respectively, in the aged rats. The serum concentration of bilirubin, an indicator of erythrocyte breakdown and/or liver function was likewise increased in these animals. In view of these findings, we suggest that the high activity of MHO and the low level of ALA-S may be a significant causative factor for the decreased microsomal concentration of heme, cytochrome-P-450 and its dependent monooxygenase activities in senescent female rats.
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PMID:Aberration of heme and hemoprotein in aged female rats. 360 51

The effects of various metals and metalloporphyrins, which are known to alter markedly heme metabolism in vivo, on the heme saturation of tryptophan pyrrolase in liver were examined. At early time points, up to 120 min, administration of CoCl2 to rats caused a rapid and marked decrease in the degree of heme saturation of tryptophan pyrrolase; in contrast, Co-protoporphyrin produced a slight increase in heme saturation of the enzyme. SnCl2 did not alter the heme saturation of tryptophan pyrrolase; however, treatment of rats with Sn-protoporphyrin, a potent competitive inhibitor of heme oxygenase activity both in vivo and in vitro, produced a rapid and complete heme saturation of tryptophan pyrrolase. In addition, upon simultaneous administration of Sn-protoporphyrin and CoCl2, Sn-protoporphyrin prevented the CoCl2-mediated decrease in heme saturation of tryptophan pyrrolase. These findings provide further evidence that the measurement of the heme saturation of tryptophan pyrrolase is a sensitive indicator of changes in the availability of heme in the "regulatory" heme pool, particularly in the immediate period after administration of compounds which are known to perturb heme metabolism in vivo.
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PMID:Tryptophan pyrrolase in heme metabolism. Comparative actions of inorganic tin and cobalt and their protoporphyrin chelates on tryptophan pyrrolase in liver. 375 72

Administration of the antimalarial agent primaquine to male rats (50 mg/kg i.p. daily for 4 days) resulted in a 30% decrease in hepatic microsomal cytochrome P-450 (P-450) content; levels of other microsomal haemoproteins were unaltered. Kinetic analysis of 2 mixed-function oxidase activities (aminopyrine N-demethylase and aniline p-hydroxylase) in primaquine-pretreated rat liver microsomes revealed a significant and similar decrease in the maximal reaction velocities of these enzymes (Vmax), but the apparent Michaelis constants (Km) were not changed. The activity of mitochondrial delta-aminolaevulinic acid synthetase (the rate-limiting step in haem biosynthesis) was normal in primaquine-pretreated rat liver but haem oxygenase activity (the rate-limiting step in haem degradation) was elevated approximately 2-fold. Haem availability for haemoprotein assembly (determined as the haem-saturation ratio of the cytosolic haemoprotein tryptophan pyrrolase) was also normal although the absolute activity of tryptophan pyrrolase was decreased after primaquine pretreatment. In order to facilitate an analysis of the P-450 isozyme profile in control and primaquine-treated rat liver, total microsomal P-450 was isolated by hydrophobic affinity chromatography on n-octylamino-Sepharose 4B. Densitometry of stained polyacrylamide gels following electrophoresis of these partially-purified P-450 fractions indicated that primaquine exposure did not selectively decrease any of the 3 protein bands in the P-450 molecular weight region (48-56 kD). These observations, when considered together, suggest that primaquine may affect P-450 and mixed-function oxidase activity by inhibition of protein synthesis. The characteristic rapid turnover rates of P-450 isozymes may predispose these haemoproteins to the toxic effects of primaquine whereas those haemoproteins that turn over less rapidly, such as cytochrome b5, appear to be less susceptible. Microsomal haem oxygenase activity may be elevated after primaquine administration since lowered haemoprotein requirements for haem could result in excess haem levels within the hepatocyte.
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PMID:Effects of primaquine on hepatic microsomal haemoproteins and drug oxidation. 379 69

Sn-protoporphyrin is a potent competitive inhibitor of heme oxygenase, the rate-limiting enzyme in heme degradation to bile pigment, and has been successfully utilized to suppress hyperbilirubinemia in a variety of experimental and naturally occurring forms of jaundice in animals and man. The compound is presumed to act in vivo primarily by inhibiting heme oxidation; thus it would be reasonable to expect that preservation of some functional moiety of cellular heme from degradation by heme oxygenase would occur after Sn-protoporphyrin administration. We have examined this question in liver by studying the heme saturation of tryptophan pyrrolase, the heme-dependent enzyme which controls the first and rate-limiting step in the catabolism of L-tryptophan. Sn-protoporphyrin, in doses (10 mumol/kg body wt) which entirely suppress neonatal hyperbilirubinemia in the experimental animal, leads to a very rapid (approximately 30-60 min) increase in the heme saturation of tryptophan pyrrolase from normal levels of approximately 50-60% to nearly 100%. The effect peaks at 1-2 h and lasts for at least 12 h. Sn-protoporphyrin is also able to block the rapid and marked decline in heme saturation of tryptophan pyrrolase elicited by inorganic cobalt, a potent inducer of heme oxygenase in liver. These findings establish clearly that after the administration of Sn-protoporphyrin in the whole animal, a functionally active heme pool, the one related to tryptophan pyrrolase, is rapidly increased in liver, confirming that the metalloporphyrin inhibits the degradation of endogenous heme by heme oxygenase.
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PMID:Sn-protoporphyrin rapidly and markedly enhances the heme saturation of hepatic tryptophan pyrrolase. Evidence that this synthetic metalloporphyrin increases the functional content of heme in the liver. 396 10

Cytochrome P450 levels are often low in the cirrhotic liver but the reason for this has not been established. Because changes in heme metabolism may reduce hepatic levels of cytochrome P450, the relationship of heme turnover to cytochrome P450 levels has been examined in rats with cirrhosis. Cirrhosis was produced by repeated carbon tetrachloride inhalation. In animals with cirrhosis, hepatic microsomal cytochrome P450 content was significantly less (32%) than in controls. Heme synthesis was assessed by measuring the activity of mitochondrial delta-amino-levulinic acid synthetase and also by determining the incorporation (within 30 min) of radiolabeled delta-aminolevulinic acid into the microsomal heme fraction. Both these parameters were normal in rats with CCl4-induced cirrhosis. In addition, the activity of microsomal heme oxygenase, the rate-limiting enzyme in catabolism of heme to bilirubin, was not altered. Cytochrome P450 heme degradation was then determined directly by injecting radiolabeled delta-aminolevulinic acid and measuring radioactivity in CO-binding particles (microsomes incubated with protease to remove cytochrome b5) prepared at various times thereafter. By this method, the degradation rate of cytochrome P450 heme did not differ between rats with cirrhosis and controls. Finally, the availability of hepatic heme for formation of hemoproteins was deemed to be satisfactory in cirrhotic liver because tryptophan pyrrolase saturation was comparable with controls, and also because heme administered in vivo did not enhance hepatic clearance of the cytochrome P450 substrate antipyrine. The failure to find defective heme biosynthesis or accelerated heme breakdown and the evidence that heme is available in amounts that do not restrict hemoprotein formation indicate that aberrant heme metabolism is not the cause of low cytochrome P450 levels in this rat model of cirrhosis.
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PMID:Hepatic heme metabolism and cytochrome P450 in cirrhotic rat liver. 400 1

We have previously suggested that an inherent defect in hepatic haem utilization was responsible for the rapid stimulation of hepatic microsomal haem oxygenase activity observed in selenium-deficient rats given phenobarbital, a well known inducer of haem formation. To test this hypothesis, hepatic haem content was deliberately raised in selenium-deficient rats by administration of either tryptophan or allylisopropylacetamide, or by injecting haem itself. We now report that selenium-deficient rats are apparently relatively less efficient in utilizing hepatic haem than normal controls. The findings detailed in the present paper thus indicate that stimulation of hepatic microsomal haem oxygenase activity is indeed a manifestation of abnormal haem utilization in selenium deficiency. This suggests a novel role for selenium in hepatic haem metabolism.
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PMID:Defective utilization of haem in selenium-deficient rat liver. 661 73

Age-related changes in heme and hemoproteins, as well as the effect of testosterone treatment on these modifications were examined in male Sprague-Dawley rats. The activity of delta-aminolevulinic acid synthase (ALA-S) and the microsomal concentration of heme in aged rats were decreased by 37% and 33%, respectively, as compared to young values. In contrast, a marked increase in the activity of microsomal heme oxygenase (MHO) was seen in these animals. In aged rats, the level of cytochrome P-450 was decreased by 37%, as compared to young values. Furthermore, the activities of benzo[a]pyrene hydroxylase and aniline hydroxylase were decreased in proportion to the microsomal content of cytocyrome P-450. Steroid delta 4-hydrogenase, an index of endogenous substrate metabolism, exhibited no changes in activity during the aging process. The level of various hemoproteins such as cytochrome b5 and tryptophan pyrrolase in aged animals remained unaltered despite the decreased hepatic concentration of heme. It is worth noting that testosterone treatment of aged castrated rats restored the level of heme and cytochrome P-450 and the altered enzymatic activities of ALA-S and MHO to the "young" condition. In view of these findings, it is concluded that the events which lead to the low level of heme and cytochrome P-450 and its dependent mixed function oxidase activity during the senescent period could be due to increased rates of MHO and diminished ALA-S activities in these animals.
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PMID:Modification of age-induced changes in heme and hemoproteins by testosterone in male rats. 665 12

Alterations in heme biosynthetic and degradative capabilities and in the activities of several heme-containing enzymes were examined in hepatic tissues of streptozotocin (STZ)-diabetic female Sprague-Dawley rats. Activities were measured 10, 30 and 90 days following the administration of STZ (65 mg/kg, i.v.). The activities of the key enzymes involved in heme synthesis, delta-aminolevulinic acid (ALA) synthase, ALA dehydratase, and uroporphyrinogen synthase, were decreased markedly in STZ-diabetic rats as compared to sham-operated animals. Furthermore, the catabolism of heme which occurs via microsomal heme oxygenase (MHO) remained unaltered in these animals. Microsomal content of heme and cytochrome P-450, and the activities of tryptophan pyrrolase and the drug-metabolizing enzymes benzo[a]pyrene (BP) hydroxylase and aniline hydroxylase, were increased in the livers of diabetic rats. By contrast, the activity of the heme-containing enzyme catalase was decreased in these animals. Cobalt chloride produced a marked increase in MHO with a concomitant decrease in microsomal content of cytochrome P-450 and its associated BP hydroxylase activity in normal as well as chronically diabetic rats. It was of interest, however, that the increase in ALA synthase that is normally produced by this metal was not seen in chronic diabetic animals. Thus, chronic diabetes produced subtle and important disruptions in cellular metabolism, which may have been the result of long-term alterations in key enzymes involved in heme synthesis.
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PMID:Heme and hemoproteins in streptozotocin-diabetic female rats. 668 50

Microsomal heme oxygenase has been purified from bovine spleen to homogeneity using DEAE-cellulose chromatography, initial hydroxyapatite chromatography, gel filtration, and repeat hydroxyapatite chromatography. The purified enzyme showed a single protein band on sodium dodecyl sulfate-polyacrylamide gel electrophoresis with a molecular weight of congruent to 31,000. It had a Km for heme of 0.93 microM, a specific activity of 6770 units/mg of protein, and a turnover number of 3.5 mol/mol of enzyme/min. Amino acid analysis of the purified enzyme revealed an abundance of glutamine and glutamic acid residues, a log tryptophan content (2 tryptophan residues/mol of enzyme), and four free sulfhydryl groups, only two of which were accessible to sulfhydryl (--SH) inactivating reagents without unfolding of the protein. Consistent with these findings, the purified enzyme had a relatively low extinction coefficient at 280 nm (E11%cm = 8.12) and was relatively resistant to inactivation by --SH inactivating reagents. NADPH-cytochrome c reductase from bovine liver was purified to homogeneity and biliverdin reductase from bovine spleen was partially purified. The heme oxygenase system was reconstituted from preparations of all three purified enzymes and, utilizing this reconstituted system, the specific sites of the inhibitory actions of --SH inactivating reagents, inorganic metals, and metalloporphyrins on the heme degrading sequence of reactions were examined. Sn-, Co-, Zn-, and Mn-protoporphyrin strongly inhibited heme degradation in a competitive manner. The Ki values for Sn-, Co-, and Zn-protoporphyrin were determined to be 0;033, 0.082, and 0.13 microM, respectively. Mg-, Ni-, and Cu-protoporphyrin had little effect on heme degradation by the reconstituted system. Metals such as Pt2+ and Hg2+ strongly inhibited the activity of the reconstituted heme oxygenase system, but the principal site of action of these metals was at the level of NADPH-cytochrome c reductase or biliverdin reductase. Similarly --SH inactivating reagents, such as p-chloromercuribenzoate, 5,5'-dithiobis-(2-nitrobenzoate), or N-ethylmaleimide inhibited the reaction catalyzed by the reconstituted heme oxygenase system principally by inhibiting the activity of NADPH-cytochrome c reductase.
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PMID:Purification and properties of bovine spleen heme oxygenase. Amino acid composition and sites of action of inhibitors of heme oxidation. 680 82


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