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PubMed1997

Cyclo-oxygenase and colon cancer: clues to the aspirin effect?

Epidemiological and experimental studies indicate an inverse relationship between the risk of colon cancer development and intake of aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs). All NSAIDs are known inhibitors of cyclo-oxygenase, the enzyme responsible for converting arachidonic acid to prostaglandins. Prostaglandins have been implicated in the pathogenesis of colon cancer and it has been suggested that the preventive effect of NSAIDs is due to inhibition of cyclo-oxygenase activity. Cyclo-oxygenase exists in two different isoforms, cyclo-oxygenase-1 and cyclo-oxygenase-2, and data obtained during the last few years have suggested that cyclo-oxygenase-2 might be involved in both human and experimental colon carcinogenesis. The purpose of this review is to provide an update on recent studies regarding cyclo-oxygenase, in particular cyclo-oxygenase-2, in relation to colon cancer in humans and in experimental models.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed2000

Ebselen lowers plasma interleukin-6 levels and glial heme oxygenase-1 expression after focal photothrombotic brain ischemia.

Heme oxygenase-1, an inducible heat shock protein, is upregulated by oxidative stress, and its expression is modulated by proinflammatory cytokines such as IL-1 and IL-6. In the present study, we investigated the effects of postlesional, orally applied ebselen, a neuroprotective antioxidant, on serum levels of IL-6 and cerebral heme oxygenase-1 expression following focal ischemia induced by photothrombosis. Ebselen (50 mg/kg body weight) was given 30 min postlesion to male Wistar rats. Animals were divided into four groups: sham-operated vehicle control (n = 9), sham-operated ebselen control (n = 8), lesioned vehicle control (n = 14), and lesioned ebselen-treated (n = 17). Ebselen treatment resulted in a significant lowering of IL-6 plasma levels (26 +/- 5 pg/ml) as compared with that seen in lesioned vehicle controls (48 +/- 9 pg/ml) at 24 h postlesion. In sham-operated rats IL-6 was not detectable. Heme oxygenase-1-positive glial cells were quantitated within topographically determined perilesional brain regions. Within the 0.5-mm-wide rim region directly associated with the lesion core, no differences in the amount of heme oxygenase-1-positive glial cells were found. However, in the more remote ipsilateral perilesional cortex, significantly fewer heme oxygenase-1-positive glial cells were present within the supragranular cortical layers of lesioned ebselen-treated rats compared to lesioned vehicle controls (P < 0.001). In sham-operated rats, no glial heme oxygenase-1 induction occurred. The results indicate that postlesional ebselen treatment lowered plasma IL-6 levels subsequent to a photothrombotic lesion concomitant with a lowering of the heme oxygenase-1 response in glial cells.

Animals↗
PubMed1988

Rat liver cytochrome P-450b, P-420b, and P-420c are degraded to biliverdin by heme oxygenase.

In this report we provide data, for the first time, demonstrating the conversion of the heme moiety of certain cytochrome P-450 and P-420 preparations, to biliverdin, catalyzed by heme oxygenase. We have used purified preparations of cytochromes P-450c, P-450b, P-450/P-420c, or P-450/P-420b as substrates in a heme oxygenase assay system reconstituted with heme oxygenase isoforms, HO-2 or HO-1, NADPH-cytochrome c (P-450) reductase, biliverdin reductase, NADPH, and Emulgen 911. With cytochrome P-450b or P-450/P-420b preparations, a near quantitative conversion of degraded heme to bile pigments was observed. In the case of cytochrome P-450/P-420c approximately 70% of the degraded heme was accounted for as bilirubin but only cytochrome P-420c was appreciably degraded. The role of heme oxygenase in this reaction was supported by the following observations: (i) bilirubin formation was not observed when heme oxygenase was omitted from the assay system; (ii) the rate of degradation of the heme moiety was at least threefold greater with heme oxygenase and NADPH-cytochrome c (P-450) reductase than that observed with reductase alone; and (iii) the presence of Zn- or Sn-protoporphyrins (2 microM), known competitive inhibitors of heme oxygenase, resulted in 70-90% inhibition of bilirubin formation.

Animals↗
PubMed1983

Synergistic induction of microsomal heme oxygenase activity in rat liver and kidney by diethyldithiocarbamate and nickel chloride.

Microsomal heme oxygenase activity was measured in liver and kidney of rats killed after administration of sodium diethyldithiocarbamate (DDC) and nickel chloride (NiCl2), singly and in combinations (DDC dosages: 0.33 to 1.33 mmol/kg, im, 17 hr before death; NiCl2 dosages: 0.125 and 0.25 mmol/kg, sc, 17 hr before death). Synergistic induction was observed at all dosage combinations. At the highest dosages of DDC and NiCl2, the dual treatments induced heme oxygenase activity 11-fold in liver and 16-fold in kidney; at the same dosages given individually, DDC induction of heme oxygenase activity was 3-fold in liver and 2-fold in kidney, and NiCl2-induction was 1.3-fold in liver and 6-fold in kidney. Synergistic induction of heme oxygenase activity in liver occurred when DDC was injected 6 hr before to 6 hr after NiCl2; synergistic induction in kidney occurred when DDC was injected 6 hr before to 3 hr after NiCl2. Actinomycin D prevented the induction of heme oxygenase activity by DDC or NiCl2, given individually; the effect of actinomycin D on synergistic induction could not be measured, since the rats all died following treatment with DDC, NiCl2, and actinomycin D. Administration of cysteine to rats, po, 18 hr before death, partially suppressed the induction of hepatic heme oxygenase activity by DDC, singly or in combination with NiCl2. Synergistic induction of hepatic heme oxygenase activity also occurred in rats that received dual injections of DDC (1.33 mmol/kg, im) and hemoglobin (0.3 g/kg, iv); the synergism of DDC and hemoglobin, although statistically significant, was small in comparison to the striking synergistic effect of DDC and NiCl2.

Animals↗
PubMed1989

Heme catabolism in cultured hepatocytes: evidence that heme oxygenase is the predominant pathway and that a proportion of synthesized heme is converted rapidly to biliverdin.

Heme oxygenase has been considered to be involved in the predominant pathway of heme degradation in vivo. However, alternative pathways involving cytochrome P-450 reductase, and lipid peroxidation, have previously been demonstrated in vitro, and studies with cultured rat hepatocytes were interpreted to show a majority of endogenous hepatic heme breakdown by non-heme oxygenase pathways. To clarify the pathway of heme breakdown in hepatocytes and the role of heme oxygenase in this process, cultured hepatocytes were pre-labelled with 5-[5-14C]aminolevulinate [( 14C]ALA). Radioactivity in heme, carbon monoxide, and bile pigments was measured for 8-24 h after the removal of [14C]ALA. In cultured chick embryo hepatocytes, which lack biliverdin reductase, the rate of production of biliverdin IXa was closely similar to the rate of catabolism of exogenous heme and radioactivity in carbon monoxide and biliverdin IXa was similar to the loss of radioactivity from endogenous heme. These results support the conclusion that heme breakdown occurred predominantly, if not solely, by heme oxygenase. Also, no evidence of non-heme oxygenase pathways was found in the presence of tin protoporphyrin, an inhibitor of heme oxygenase or mephenytoin, an inducer of both cytochrome P-450 and heme oxygenase. Similarly, in untreated cultured rat hepatocytes, radioactivity in carbon monoxide corresponded with loss of radioactivity in endogenous heme. In other experiments with chick hepatocyte cultures, rates of heme synthesis and breakdown were measured, and data were fitted to various models of hepatic heme metabolism. The results observed were consistent only with models in which an appreciable fraction (control cells, 17%, mephenytoin treated cells, 41%) of the newly synthesized heme was degraded rapidly to biliverdin.

Animals↗
PubMed1999

Induction of heme oxygenase-1 as a response in sensing the signals evoked by distinct nitric oxide donors.

To gain insights into the cellular responses evoked by nitric oxide (NO), we have studied the effects of NO donors with distinct chemistries on the expression of heme oxygenase-1 mRNA by northern blot analysis. The expression levels of heme oxygenase-1 mRNA were increased significantly in DLD-1 human colorectal adenocarcinoma cells by treatment with each of three NO donors: sodium nitroprusside (SNP), S-nitroso-L-glutathione (GSNO), and 3-morpholinosydnonimine (SIN-1). A combination of SIN-1 plus SNP or GSNO additively increased heme oxygenase-1 mRNA expression, whereas synergistic induction was seen with SNP plus GSNO. The SNP-mediated induction was not affected noticeably by extracellular superoxide dismutase, catalase, or mannitol, while the induction by SIN-1 was attenuated by superoxide dismutase. Thus, the SNP-mediated induction of heme oxygenase-1 mRNA expression may be independent of reactive oxygen species, and the induction by SIN-1 is mediated partly by peroxynitrite, which is generated by immediate reaction of NO and superoxide anion. Transient transfection assays suggested that treatment with SNP, but not with GSNO or SIN-1, increased the expression of a reporter gene through a cis-acting element, including the cadmium-responsive element, of the human heme oxygenase-1 gene. These results suggest that SNP induces heme oxygenase-1 mRNA expression through a mechanism different from that for GSNO or SIN-1. We therefore propose that induction of heme oxygenase-1 represents a common cellular response in sensing the signals evoked by distinct NO donors.

Adenocarcinoma↗
PubMed1999

Iron overload upregulates haem oxygenase 1 in the lung more rapidly than in other tissues.

Haem oxygenase-1 is upregulated by numerous insults, including oxidative stress, and under such circumstances it is considered to be a protective stratagem. We have measured the haem oxygenase-1 expression in heart, lung and liver tissues of control and iron-overloaded rats. Lung tissue from iron-overloaded rats displayed a significant increase in the haem oxygenase-1 protein but no changes in haem oxygenase-1 mRNA. Conversely, heart tissue showed a significant increase in haem oxygenase-1 mRNA but no changes in haem oxygenase-1 protein. We conclude that during oxidative stress caused by iron overload, lung tissue responds with a rapid upregulation of haem oxygenase-1 levels.

Animals↗
PubMed2003

Expression and characterization of cyanobacterium heme oxygenase, a key enzyme in the phycobilin synthesis. Properties of the heme complex of recombinant active enzyme.

An efficient bacterial expression system of cyanobacterium Synechocystis sp. PCC 6803 heme oxygenase gene, ho-1, has been constructed, using a synthetic gene. A soluble protein was expressed at high levels and was highly purified, for the first time. The protein binds equimolar free hemin to catabolize the bound hemin to ferric-biliverdin IX alpha in the presence of oxygen and reducing equivalents, showing the heme oxygenase activity. During the reaction, verdoheme intermediate is formed with the evolution of carbon monoxide. Though both ascorbate and NADPH-cytochrome P450 reductase serve as an electron donor, the heme catabolism assisted by ascorbate is considerably slow and the reaction with NADPH-cytochrome P450 reductase is greatly retarded after the oxy-heme complex formation. The optical absorption spectra of the heme-enzyme complexes are similar to those of the known heme oxygenase complexes but have some distinct features, exhibiting the Soret band slightly blue-shifted and relatively strong CT bands of the high-spin component in the ferric form spectrum. The heme-enzyme complex shows the acid-base transition, where two alkaline species are generated. EPR of the nitrosyl heme complex has established the nitrogenous proximal ligand, presumably histidine 17 and the obtained EPR parameters are discriminated from those of the rat heme oxygenase-1 complex. The spectroscopic characters as well as the catabolic activities strongly suggest that, in spite of very high conservation of the primary structure, the heme pocket structure of Synechocystis heme oxygenase isoform-1 is different from that of rat heme oxygenase isoform-1, rather resembling that of bacterial heme oxygenase, H mu O.

Amino Acid Sequence↗
PubMed1987

Dual control mechanism for heme oxygenase: tin(IV)-protoporphyrin potently inhibits enzyme activity while markedly increasing content of enzyme protein in liver.

Tin(IV)-protoporphyrin (Sn-protoporphyrin) potently inhibits heme degradation to bile pigments in vitro and in vivo, a property that confers upon this synthetic compound the ability to suppress a variety of experimentally induced and naturally occurring forms of jaundice in animals and humans. Utilizing rat liver heme oxygenase purified to homogeneity together with appropriate immunoquantitation techniques, we have demonstrated that Sn-protoporphyrin possesses the additional property of potently inducing the synthesis of heme oxygenase protein in liver cells while, concurrently, completely inhibiting the activity of the newly formed enzyme. Substitution of tin for the central iron atom of heme thus leads to the formation of a synthetic heme analogue that regulates heme oxygenase by a dual mechanism, which involves competitive inhibition of the enzyme for the natural substrate heme and simultaneous enhancement of new enzyme synthesis. Cobaltic(III)-protoporphyrin (Co-protoporphyrin) also inhibits heme oxygenase activity in vitro, but unlike Sn-protoporphyrin it greatly enhances the activity of the enzyme in the whole animal. Co-protoporphyrin also acts as an in vivo inhibitor of heme oxygenase; however, its inducing effect on heme oxygenase synthesis is so pronounced as to prevail in vivo over its inhibitory effect on the enzyme. These studies show that certain synthetic heme analogues possess the ability to simultaneously inhibit as well as induce the enzyme heme oxygenase in liver. The net balance between these two actions, as reflected in the rate of heme oxidation activity in the whole animal, appears to be influenced by the nature of the central metal atom of the synthetic metalloporphyrin.

Animals↗
PubMed1998

Mechanism of sodium arsenite-mediated induction of heme oxygenase-1 in hepatoma cells. Role of mitogen-activated protein kinases.

Heme oxygenase-1 is an inducible enzyme that catalyzes heme degradation and has been proposed to play a role in protecting cells against oxidative stress-related injury. We investigated the induction of heme oxygenase-1 by the tumor promoter arsenite in a chicken hepatoma cell line, LMH. We identified a heme oxygenase-1 promoter-driven luciferase reporter construct that was highly and reproducibly expressed in response to sodium arsenite treatment. This construct was used to investigate the role of mitogen-activated protein (MAP) kinases in arsenite-mediated heme oxygenase-1 gene expression. In LMH cells, sodium arsenite, cadmium, and heat shock, but not heme, induced activity of the MAP kinases extracellular-regulated kinase (ERK), c-Jun N-terminal kinase (JNK), and p38. To examine whether these MAP kinases were involved in mediating heme oxygenase-1 gene expression, we utilized constitutively activated and dominant negative components of the ERK, JNK, and p38 MAP kinase signaling pathways. Involvement of an AP-1 site in arsenite induction of heme oxygenase-1 gene expression was studied. We conclude that the MAP kinases ERK and p38 are involved in the induction of heme oxygenase-1, and that at least one AP-1 element (located -1576 base pairs upstream of the transcription start site) is involved in this response.

Animals↗
PubMed1984

An induction of heme oxygenase and its possible relation to the decrease of cytochrome P-450 content during liver regeneration.

The alterations of various enzymes responsible for drug metabolism and heme metabolism were examined in regenerating livers of male rats. Microsomal cytochrome P-450 content and aminopyrine demethylase activity were significantly decreased during liver regeneration. In contrast, microsomal heme oxygenase activity was markedly increased under the identical conditions. The increased heme oxygenase activity which appeared within 4 h and reached maximum at 1 d after partial hepatectomy was sustained for 5 d. In sham-operated rats, the changed patterns of these parameters were similar, but to a lesser extent as compared to partially hepatectomized rats. The increase of heme oxygenase activity following partial hepatectomy was blocked by the administration of cycloheximide or actinomycin D. Other enzymes involved in heme synthesis did not change appreciably during liver regeneration. The inverse relationship between the decrease of cytochrome P-450 content and the increase of heme oxygenase activity was also observed in female rats and male mice. These findings suggest that the increase of heme oxygenase activity in regenerating rodent liver would be correlated to the decrease of cytochrome P-450 content. Adrenalectomy enhanced the increase of heme oxygenase activity following partial hepatectomy, though the decrease of cytochrome P-450 content was less extensive under the experimental conditions. The results also suggest that the inverse relationship between the increase of heme oxygenase activity and the decrease of cytochrome P-450 content would be a biochemical phenomenon seen in regenerating liver and that the phenomenon would not be simply due to the surgical stress to the animals.

Adrenalectomy↗
PubMed1996

Cloning and expression of cDNA for soluble form of rat heme oxygenase-1.

Heme oxygenase catalyzes the oxidation of heme to biliverdin and carbon monoxide. The gene encoding the truncated soluble rat heme oxygenase-1 (Metl-Pro267) was cloned. The enzyme protein was expressed in E. coli JM109 and purified to homogeneity. The molecular weight of the recombinant enzyme was 30 kDa as assessed by SDS-polyacrylamide gel electrophoresis. From a 3-L culture, about 90 mg of the purified enzyme was routinely obtained. The dependency of the heme oxygenase reaction catalyzed by the soluble enzyme on the NADPH-cytochrome P-450 reductase concentrations and the effect of catalase on the reaction were examined to compare with the purified membrane-bound form of heme oxygenase-1 (Yoshida and Kikuchi, 1978b). The activity of the soluble enzyme was inhibited at high concentrations of NADPH-cytochrome P-450 reductase and the inhibition was not alleviated by addition of catalase unlike the membrane-bound form. The ferric iron of the heme-heme oxygenase complex was in a typical high spin state at acidic to neutral pH (pH 6.5-7.0) but conversion to low spin state was observed at basic pH (pH 9-10). The heme bound to heme oxygenase was converted to biliverdin at a stoichiometric ratio of unity in the presence of NADPH-cytochrome P-450 reductase system. During the heme degradation of the heme-heme oxygenase complex under atmospheric oxygen, several intermediates, that is, oxygenated heme and verdoheme, were spectrally discriminated.

Animals↗
PubMed1990

Isolation, characterization, and expression in Escherichia coli of a cDNA encoding rat heme oxygenase-2.

In a recent study (Cruse, I., and Maines, M.D. (1988) J. Biol. Chem. 263, 3348-3353), we reported the isolation of a small cDNA fragment encoding a portion of heme oxygenase-2 through immunological screening of a rat testis cDNA library in lambda gt11. We have now used this 274-base pair (bp) cDNA fragment as a hybridization probe for rescreening of the same library, and have thereby recovered a number of additional positive isolates. Of these, three candidates of approximately 900, 1100, and 1300 bp, respectively, were subsequently subcloned and sequenced. Although differing in length, the sequences of these clones were found to be otherwise identical. Moreover, the length of isolate 18B, 1284 bp, corresponded well with that of the single mRNA species (approximately 1300-1350 nucleotides) detected through Northern blot hybridization analysis of rat testis total and poly(A)+RNA. This full- or near full-length cDNA encodes a 315-amino acid protein with a molecular weight of 35,757, in good agreement with the 36,000 estimated molecular weight of heme oxygenase-2. When expressed in Escherichia coli, cDNA encodes a protein that cross-reacts with heme oxygenase-2 antiserum (as assayed by Western immunoblotting) and yields high levels of heme oxygenase activity in bacterial soluble cell extracts. Finally, computer analysis of the heme oxygenase-2 cDNA sequence indicates that the predicted amino acid sequence and hydropathy profile of the heme oxygenase-2 protein exhibit similarity with heme oxygenase-1.

Amino Acid Sequence↗
PubMed1988

Algal heme oxygenase from Cyanidium caldarium. Partial purification and fractionation into three required protein components.

Enzymatic heme oxygenase activity has been partially purified from extracts of the unicellular red alga Cyanidium caldarium, and the macromolecular components have been separated into three protein fractions, referred to as Fractions I, II, and III, by serial column chromatography through DEAE-cellulose and Reactive Blue 2-Sepharose. Fraction I is retained by DEAE-cellulose at low salt concentration and eluted by 1 M NaCl. Fraction II is retained by Blue Sepharose at low salt concentration and eluted by 1 M NaCl. Fraction III is retained on 2',5'-ADP-agarose and eluted by 1 mM NADPH, while Fraction II is not retained on ADP-agarose. Fractions I-III, have Mr values of 22,000, 38,000, and 37,000, respectively (all +/- 2,000), as determined by Sephadex gel filtration chromatography. In vitro heme oxygenase activity requires the presence of all three fractions, plus substrate, O2, reduced pyridine nucleotide, and another reductant. Ascorbate, isoascorbate, and phenylenediamine serve equally well as the second reductant, but hydroquinone can also be used, with lower activity resulting. Fractions I-III are heat sensitive and inactive by Pronase digestion. Fraction I has a visible absorption spectrum similar to that of ferredoxin and is bleached by dithionite reduction or incubation with p-hydroxymercuribenzoate. Fraction I can be replaced by commercially available ferredoxin derived from the red alga Porphyra umbilicalis, and to a smaller extent, by spinach ferredoxin. Fraction III contains ferredoxin-linked cytochrome c reductase activity and can be partially replaced by spinach ferredoxin-NADP+ oxidoreductase. Reconstituted heme oxygenase and ferredoxin-linked cytochrome c reductase activities are both abolished if Fraction I or III is preincubated with 0.1 mM p-hydroxymercuribenzoate, but heme oxygenase activity is only slightly affected if Fraction II is preincubated with p-hydroxymercuribenzoate. Preincubation of Fraction II with 0.5 mM diethylpyrocarbonate inactivates heme oxygenase in the reconstituted system, and 10 microM mesohemin partially protects this Fraction against diethylpyrocarbonate inactivation. Algal heme oxygenase is inhibited 80% by 2 microM Sn-protoporphyrin even in the presence of 20 microM mesohemin. Fraction II is rate limiting in unfractionated and reconstituted incubation mixtures. None of the three cell fractions could be replaced by bovine spleen microsomal heme oxygenase or NADPH-cytochrome P450 reductase.

Catalase↗
PubMed1987

Transcriptional control of rat heme oxygenase by heat shock.

A heat shock element is located in the 5'-flanking region of the rat heme oxygenase gene (HO gene). The incubation of rat glioma cells at 42 degrees C or with hemin at 37 degrees C increased the levels of heme oxygenase mRNA within 1 h and produced a maximum at 3 h (at least a 20-fold increase). In both treatments, the heme oxygenase activity started to increase after a lag period of about 1 h and reached a maximum value at 5 h. There was an apparent additive effect of both treatments on the heme oxygenase induction. Studies with actinomycin D and cycloheximide suggested that both heat shock and hemin acted at the transcriptional level to induce heme oxygenase. Therefore, we analyzed the transient expression of chimeric fusion genes harboring the promoter of the rat HO gene ligated to the Escherichia coli gene gpt in rat glioma cells and in K1735 mouse amelanotic melanoma cells. The 5'-flanking region of the rat HO gene bearing the heat shock element conferred the heat inducibility of gpt RNA production in both cell lines; however, hemin treatment did not induce gpt RNA. These results indicate that rat heme oxygenase is a heat shock protein and that hemin induces heme oxygenase through a different mechanism from heat shock.

Animals↗
PubMed1980

Intracellular site of synthesis of microsomal heme oxygenase in pig spleen.

In the pig spleen the specific activity of heme oxygenase was two to three times higher in smooth microsomes than in rough microsomes, whereas the total heme oxygenase activities recovered in the two microsomal fractions were similar. Free and bound polysomes were isolated from pig spleen and nascent peptides on these polysomes were analyzed by employing [3H]puromycin and a heme oxygenase-specific rabbit antibody (IgG). It was shown that free polysomes are the major site of heme oxygenase synthesis. In addition, cell-free synthesis of heme oxygenase was performed in a reticulocyte lysate system with free and bound polysomes isolated from pig spleen, and the results obtained again indicated that heme oxygenase is synthesized predominantly on free polysomes. The heme oxygenase newly synthesized on free polysomes may be incorporated first into the rough portion of endoplasmic reticulum either before or after its release from polysomes, although the specific activity of this enzyme at the steady state is considerably higher in the smooth region.

Animals↗
PubMed1982

Gas-chromatographic assay for heme oxygenase activity.

We have developed an improved assay for microsomal heme oxygenase activity, based on the enzymic release of CO from the alpha-methene bridge of hemin and the quantitation of CO by gas chromatography. The within-run coefficient of variation (CV) of heme oxygenase assays in microsomes from rat tissues (liver, kidney) averaged 8%; the between-run CV averaged 15%. The detection limit for heme oxygenase activity was approximately 1 nmol/h per milligram of microsomal protein. Gas-chromatographic assays of heme oxygenase activities in rat tissues correlated well (r = 0.94) with results by a spectrophotometric assay based on bilirubin production. In untreated rats, heme oxygenase activity averaged 7 +/- 3 nmol/h per milligram of protein (n = 36) in kidney microsomes and 14 +/- 5 nmol/h per milligram of protein (n = 17) in liver microsomes. Heme oxygenase activity was increased 10-fold in kidney microsomes and threefold in liver microsomes from rats killed 17 h after subcutaneous injection of NiCl2 (0.5 mmol/kg body wt). These findings illustrate the efficacy of the gas-chromatographic assay for measuring xenobiotic effects on heme oxygenase activity.

Animals↗
PubMed1996

Induction of the haem oxygenase gene expression during the reperfusion of ischemic rat myocardium.

A variety of stress including oxidative stress, hyperthermia and heavy metals can induce the expression of haem oxygenase in mammalian tissue. In this study we examined whether an ischemic stress could induce haem oxygenase in heart. Isolated perfused rat hearts were subjected to either 5 or 20 min of ischemia followed by 15, 30, 45 and 60 min of reperfusion in each case. The results of our study indicate that haem oxygenase is not induced by ischemia, but can be induced by reperfusion. The induction of haem oxygenase is a function of the duration of reperfusion. This induction can be blocked by pre-perfusing the hearts with oxygen free radical scavengers, superoxide dismutase (SOD) and catalase. Haem oxygenase was also induced in the hearts by perfusing them with oxygen free radical generating system. This induction was also blocked by SOD and catalase. Immunohistochemical localization revealed that haem oxygenase-1 is primarily accumulated in the perivascular region and in the cardiomyocytes. This suggests that it is oxygen free radicals that is produced during the reperfusion is the stimulus for the expression of haem oxygenase in the ischemic/reperfused myocardium.

Animals↗