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)

The effects of oral cadmium administration on heme oxygenase activity and cytochrome P-450-dependent drug metabolism in intestinal epithelium were examined in male Sprague-Dawley rats. Cadmium chloride was administered via drinking water (0, 5 or 50 ppm cadmium) for 5 or 30 days, and heme oxygenase, 7-ethoxycoumarin O-deethylase (ECOD), 7-ethoxyresorufin O-deethylase (EROD) and cytochrome P-450 were measured in the liver and in the epithelium of the proximal region of the small intestine. Cadmium exposure produced a marked, dose-related induction of intestinal heme oxygenase (up to 300% of control levels) in the small intestine at both time points examined. Concomitant decreases in intestinal ECOD (70%) and EROD (65%) activities were also observed, with a 65% decline in cytochrome P-450 levels at 30 days as compared with controls. Oral cadmium exposure, however, did not affect heme catabolism or cytochrome P-450 function in the liver, even at the highest concentration (50 ppm) administered, although cadmium levels accumulated in a dose-related manner in the liver as well as in the small intestine. Systemic absorption of cadmium was limited, as reflected by the relatively low accumulation of cadmium in the liver at 5 days (approximately 20 micrograms/g), as compared with the levels present in small intestine at this time ponit (approximately 100 micrograms/g). These findings emphasize the sensitivity of cytochrome P-450-dependent drug metabolism in small intestinal epithelium to orally ingested cadmium, and highlight the vulnerability of this tissue to low-dose exposure to this metal.
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PMID:Induction of heme oxygenase in the small intestinal epithelium: a response to oral cadmium exposure. 203 Dec 53

The effect of Co(NO3)2, CdSO4, NiSO4, ZnSO4, and HgCl2 (given repeatedly in subtoxic doses in the drinking water for 30 days) on rat liver monooxygenases was studied in experiments on male Wistar rats. The salts of Co, Cd, and Zn increased the activity of benzphetamine-N-demethylase, the content of cytochrome P-450 and microsomal heme. The data suggest that these salts exert an enzyme-inducing effect on the hepatic monooxygenases. The same metal salts (Co, Cd, and Zn) increased the activity of delta-aminolevulinic acid (ALA) synthetase and decreased that of heme oxygenase. The increased cytochrome P-450 content is probably due to the increased synthesis and the decreased breakdown of this hemoprotein. HgCl2 and NiSO4 did not exert an enzyme-inducing action. The lack of change in the activity of NADPH-cytochrome c reductase and cytochrome b5 (except for ZnSO4) suggests that these components of the electron transport chain are not likely to be involved in the enzyme-inducing action of the heavy metal salts.
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PMID:On the mechanism of the enzyme-inducing action of some heavy metal salts. 391 90

The administration of organotin compounds to rats in single doses causes a significant and prolonged induction of haem oxygenase and a sustained decrease in haemoprotein content in the liver. The extent of induction of hepatic haem oxygenase varied between 3 and 5-fold at 72h after a single injection of water-insoluble organotins of differing structure. The alterations in haem metabolism produced by tricyclohexyltin hydroxide were studied in detail. The effects were dose-dependent, with doses as low as 3.75 mg/kg body wt. resulting in significant induction of haem oxygenase and a decrease in cytochrome P-450 and cytochrome b5 contents at 72h in the liver. The effects with time of a single dose of tricyclohexyltin on various parameters of liver haem metabolism were also examined. The organotin produced a substantial and very prolonged induction of haem oxygenase accompanied by a steady decline in cytochrome P-450 content for periods up to 8 days. The long duration of action of these organotins with respect to induction of haem oxygenase and depletion of cellular haemoprotein content provides a highly sensitive metabolic system with which to define further the toxic potential of organometals as well as to study the adaptive responses in liver to long-term perturbations of haem metabolism by foreign chemicals.
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PMID:Prolonged induction of hepatic haem oxygenase and decreases in cytochrome P-450 content by organotin compounds. 689 90

Biliverdins formed from heme by a microsomal preparation and a reconstituted heme oxygenase system were each converted to their dimethyl esters and analyzed for isomeric composition by reversed-phase high-performance liquid chromatography, using a column of mu Bondapak C18 (Waters Associates); on this column, the dimethyl esters of four biliverdin IX isomers, that is IX alpha, IX beta, IX gamma, and IX delta, have been shown to be eluted separately in the order IX alpha, IX beta, IX delta, and IX gamma, when developed with methanol/water. The analysis indicated that the enzymatically formed biliverdins were exclusively IX alpha; the elution profile exhibited no other significant elution peak due to other biliverdin isomers. It was concluded that the heme oxygenase system cleaves the heme ring specifically at the alpha-methene bridge to yield biliverdin IX alpha.
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PMID:Identification of the product of heme degradation catalyzed by the heme oxygenase system as biliverdin IX alpha by reversed-phase high-performance liquid chromatography. 689 13

Reports of the beneficial effects of large doses of ascorbic acid have stressed its water solubility and non-toxic properties. In this study male guinea pigs, dosed with 150 mg twice daily, ascorbic acid, demonstrated no differences in effect on liver weight, body weight or hepatic total protein when compared with controls. The activities of NADPH-dependent cytochrome c reductase, N-demethylase (Type I) and O-de-ethylase enzymes (Type II) remained unaffected, but the activity of the Type I hydroxylating enzyme, biphenyl-4-hydroxylase, and the amounts of cytochromes P-450 and b5 were significantly reduced. Total microsomal haem proteins were reduced and mirrored the effects in cytochromes P-450 and b5. The rate-limiting enzyme in haem synthesis, delta-amino-laevulinic acid synthetase, rose in the ascorbic acid group and this was associated with a fall in activity of the haem degrading enzyme, microsomal haem oxygenase. Thus, large amounts of ascorbic acid have similar effects to those found in scorbutic animals and appear to interfere with the construction of the cytochrome P-450 molecule.
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PMID:Effect of large doses of ascorbic acid on the mixed function oxidase system in guinea pig liver. 709 49

Endogenous carbon monoxide (CO), produced by haem oxygenase (HO), may play a role in hippocampal long-term potentiation (LTP). Its role in learning and memory in intact animals is less well known. Tin protoporphyrin (Sn-PP; 25 mg kg-1, i.p.) effectively but transiently inhibited HO activity in brain homogenates, and improved acquisition in the Morris water maze. Locomotor activity was unaffected, indicating a behavioural specificity of the learning effect. The analogue zinc protoporphyrin (25 mg kg-1, i.p.), which does not pass the blood-brain barrier, did not affect learning. If the observed memory effect is related to inhibition of HO, the role of CO in spatial learning may be different from that suggested by LTP studies.
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PMID:Modulation of carbon monoxide production and enhanced spatial learning by tin protoporphyrin. 748 26

Electronic and resonance Raman spectroscopic studies are reported for the His25Ala mutant of human liver heme oxygenase (HO) and its complex with heme. In the oxidized (ferric) form of the enzyme.substrate complex, the heme is shown to be in a high-spin, five-coordinate state. This is distinct from the same complex in the wild-type enzyme in which the heme is six-coordinate, ligated to a proximal histidine and a water molecule in an environment reminiscent of aquometmyoglobin. The reduced (ferrous) form of the complex of the H25A heme oxygenase mutant has lost the very prominent resonance Raman band at approximately 217 cm-1 seen in the wild-type complex that has been unambiguously assigned to the proximal Fe-N(His) vibrational frequency [Sun et al. (1993) Biochemistry 32, 14151; Takahashi et al. (1994) Biochemistry 33, 1010]. The absence of this band in the spectrum of the mutant protein definitively identifies His 25 as the proximal ligand of the heme substrate. Furthermore, this ferrous heme-H25A HO complex exists as an equilibrium mixture between a five-coordinate, high-spin species and a four-coordinate, intermediate-spin species. Although the H25A mutant protein shows no heme oxygenase activity, the heme is competent to bind carbon monoxide. Studies of the CO adduct of the H25A HO complex show v(CO) and v(Fe-CO) frequencies at 1960 and 529 cm-1, respectively, that are characteristic of a hydrophobic carbon monoxide binding site on a heme with a weak proximal ligand.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Identification of histidine 25 as the heme ligand in human liver heme oxygenase. 794 84

The resonance Raman spectra of ferric and ferrous forms of the heme-heme oxygenase (HO) complex (isoform 1) clarify several structural features of the catalytic active site. Isotopic substitution studies of the central iron atom of the heme demonstrate that the line at 218 cm-1 in the ferrous ligand-free form of the complex originates from the iron-histidine stretching mode. The presence of a Raman line at this frequency confirms that the fifth ligand coordinating to the heme is a neutral imidazole from a histidine residue. The modes associated with CO in the carboxy derivative of the ferrous enzyme complex have typical frequencies of histidine-bound heme proteins such as myoglobin. In the ferric form of the complex, at alkaline pH, hydroxide is identified as the bound exogenous ligand, and at neutral pH we infer that water is bound. Thus, the coordination of the heme-HO complex is the same as that in myoglobin. However, in a comparison of the low-frequency vibrational modes in the resonance Raman spectrum of the heme-HO complex to those of myoglobin, the spectra are found to be very different, indicating that the interactions between the heme and its amino acid pocket in these two proteins are quite different. The neutral imidazole may play several important roles in the physiological function of the heme-HO complex.
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PMID:Heme-heme oxygenase complex: structure and properties of the catalytic site from resonance Raman scattering. 818 Jan 75

The binding of ferrous and ferric hemes and manganese(II)- and manganese(III)-substituted hemes to heme oxygenase has been investigated by optical absorption, resonance Raman, and EPR spectroscopy. The results are consistent with the presence of a six-coordinate heme moiety ligated to an essential histidine ligand and a water molecule. The latter ionizes with a pKa approximately 8.0 to give a mixture of high-spin and low-spin six-coordinate hydroxo adducts. Addition of excess cyanide converts the heme to a hexacoordinate low-spin species. The resonance Raman spectrum of the ferrous heme-heme oxygenase complex and that of the Mn(II)protoporphyrin-heme oxygenase complex shows bands at 216 and 212 cm-1, respectively, that are assigned to the metal-histidine stretching mode. The EPR spectrum of the oxidized heme-heme oxygenase complex has a strongly axial signal with g parallel of approximately 6 and g perpendicular approximately 2. 14NO and 15NO adducts of ferrous heme-heme oxygenase exhibit EPR hyperfine splittings of approximately 20 and approximately 25 Gauss, respectively. In addition, both nitrosyl complexes show additional superhyperfine splittings of approximately 7 Gauss from spin-spin interaction with the proximal histidine nitrogen. The heme environment in the heme-heme oxygenase enzyme-substrate complex has spectroscopic properties similar to those of the heme in myoglobin. Hence, there is neither a strongly electron-donating fifth (proximal) ligand nor an electron-withdrawing network on the distal side of the heme moiety comparable to that for cytochromes P-450 and peroxidases. This observation has profound implications about the nature of the oxygen-activating process in the heme-->biliverdin reaction that are discussed in this paper.
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PMID:Resonance Raman and EPR spectroscopic studies on heme-heme oxygenase complexes. 826 Apr 99

His-25 and His-132 are the primary candidates for the proximal heme iron ligand in heme oxygenase isozyme-1 (HO-1). The unambiguous spectroscopic demonstration that His-25 is the proximal iron ligand leaves the role of His-132 uncertain. Absorption and resonance Raman spectroscopy are used here to establish that mutation of His-132 to an alanine, glycine, or serine does not alter the histidine-iron bond, but results in the loss of the water molecule coordinated to the distal side of the iron in the wild-type enzyme-substrate complex. The His-132 mutations also (a) destabilize the ferrous-O2 complex with respect to autoxidation, which should result in partial uncoupling of NADPH consumption from heme oxidation, and (b) decrease the affinity of the enzyme for heme. The catalytic activity of the protein is decreased but not suppressed by these mutations: the H132G and H132A mutants retain 40-50% and the H132S mutant 20% of the activity of the wild-type protein. His-132, however, is required for catalytic turnover of the protein with H2O2. These results place His-132 close to the iron on the distal side of the heme pocket and indicate that His-132 facilitates, but is not absolutely required for, the catalytic turnover of HO-1.
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PMID:Heme oxygenase (HO-1): His-132 stabilizes a distal water ligand and assists catalysis. 854 75


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