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PubMed2006

Haem oxygenase-1 expression and coronary heart disease--association between levels of haem oxygenase-1 expression and angiographic morphology as well as the quantity of coronary lesions.

OBJECTIVE: The aim of this paper was to investigate the association between levels of HO-1 expression and angiographic morphology as well as the quantity of coronary lesions in patients with coronary heart disease (CHD). METHODS: 110 patients with CHD were diagnosed by coronary angiography which contained coronary lesions in some way. Firstly, the patients were divided into 3 groups according to the angiographic morphology of their coronary lesions: type I (smooth borders) group (n1= 36), type II (irregular borders) group (n2= 48) and type III (long and irregular lesions) group (n3= 26). Secondly, the patients were split into a further 3 groups, named: single-vessel group (SV, 38 cases), double-vessel group (DV, 44 cases) and multi-vessel group (MV, 28 cases) according to the number of coronary lesions. Another 30 patients with normal coronary arteries (diagnosed by coronary angiography) were selected as the control group. The levels of HO-1 protein expression in monocytes and lymphocytes from the subjects were tested by immunohistochemistry and Western blot. A computer picture analysing system was also used to measure the levels of HO-1 protein expression. RESULTS: HO-1 protein was located in cell plasma and the levels of HO-1 protein expression in patients with CHD were significantly higher than in those without CHD (p < 0.01). There were significant differences of HO-1 expression among patients with CHD. Patients with type III lesions had the highest levels, followed by those with type II lesions and the lowest levels were found in patients with type I lesions (p < 0.01). Also, levels of HO-1 protein expression in patients with multi-vessel disease and double-vessel disease were significantly higher than in those with single-vessel disease (p < 0.01). CONCLUSIONS: There is a higher expression of HO-1 in patients with CHD and the levels of HO-1 protein are associated with severity of CHD angiographically.

Aged↗
PubMed1990

Regulation of heme oxygenase gene expression by cobalt in rat liver and kidney.

The effect of heavy metals such as cobalt chloride and the corresponding metalloporphyrin on the transcription of the heme oxygenase gene in tissues was examined using cDNA for rat heme oxygenase as the probe. An increase in heme oxygenase mRNA level was observed in response to cobalt chloride and cobalt protoporphyrin treatment in both liver and kidney. Quantitative evaluation of the heme oxygenase transcript was obtained by determining the intensity of mRNA bands by scanning densitometry, and indicated that cobalt chloride increased heme oxygenase mRNA by 40-60-fold after 2 h of metal exposure. Accumulation of heme oxygenase mRNA after cobalt chloride administration was prevented by co-administration of actinomycin D or cycloheximide. These results indicate that the increased expression of heme oxygenase by cobalt chloride required de novo protein synthesis and was regulated at the transcriptional level. The time course of heme oxygenase transcript accumulation following administration of cobalt protoporphyrin was different from that of cobalt chloride. There was a sharp increase in heme oxygenase mRNA after cobalt chloride administration at 2 h and cobalt protoporphyrin at 10 h. Heme, to which cobalt protoporphyrin is structurally analogous, acted as a potent inducer of heme oxygenase transcripts in both liver and kidney. Variation in heme oxygenase mRNA levels resulting from enhanced transcription of the heme oxygenase gene was evaluated by nuclear runoff assay using isolated rat liver nuclei after cobalt chloride administration. Quantification of specific nuclear RNAs labeled during the in vitro transcription revealed active heme oxygenase gene transcription in liver nuclei from cobalt-chloride-treated rats. Transcription of heme oxygenase is greatly increased within 1 h of administration of cobalt chloride in rat liver, as evidenced by the level of [alpha-32P]UTP incorporation into nuclear RNA. The transcription was increased by 40-fold after 3 h of cobalt chloride administration. The activation of the heme oxygenase gene by metal ions is the most rapid transcriptional response to heavy metals yet described and highlights the regulatory role of heme oxygenase in heme degradation during deviating environmental conditions. On the other hand, cobalt protoporphyrin and heme arginate increase transcription of the heme oxygenase gene in a similar pattern but at a slower rate than that of the heavy metal, suggesting that the heme oxygenase promotor region may contain additional elements conferring the inducing effect of these two agents.

Animals↗
PubMed2006

Heme oxygenase-1 protects brain from acute excitotoxicity.

Heme oxygenase is a rate-limiting enzyme that degrades heme, a pro-oxidant, into carbon monoxide, iron, and bilirubin. Heme oxygenase has two active isoforms: heme oxygenase-1 and heme oxygenase-2. Heme oxygenase-1 can be induced by various insults. Several investigators have postulated that it has cytoprotective activities, although its role in the nervous system is not fully understood, especially considering that normally heme oxygenase-2 accounts for the vast majority of heme oxygenase activity in the brain. Here, the basal effect of heme oxygenase-1 was investigated in acute glutamatergic excitotoxicity to test the hypothesis that N-methyl-D-aspartate-induced acute toxicity in brain is attenuated by heme oxygenase-1. N-methyl-D-aspartate was unilaterally injected into the striatum of wildtype and heme oxygenase-1 knockout mice. After 48 h, brains were harvested, sectioned, and stained with Cresyl Violet to measure the lesion size. Lesion volume was significantly (P<0.05) greater in brains of heme oxygenase-1 knockout mice (15.2+/-3.1 mm(3); n=10) than in those of wildtype mice (6.2+/-1.5 mm(3); n=11). In addition, Western blot analysis indicated no detectable differences between wildtype and heme oxygenase-1 knockout mouse brains in the levels of the glutamate or N-methyl-D-aspartate receptors studied. To test whether heme oxygenase-1 could specifically protect neurons, mouse primary neuronal cell cultures of wildtype and heme oxygenase-1 knockout mice were treated with or without N-methyl-D-aspartate. Cell viability of the heme oxygenase-1 knockout neurons was significantly less than that of wildtype neurons at each of the N-methyl-D-aspartate concentrations tested (12.8+/-1.3%, 16.0+/-1.4%, and 18.4+/-1.8% at 30, 100, and 300 microM N-methyl-D-aspartate, respectively). These results indicate that heme oxygenase-1 provides neuroprotection against acute excitotoxicity and suggest that potential intervention that can increase heme oxygenase-1 activity within the brain should be considered as a therapeutic target in acute and potentially chronic neurological disorders.

Animals↗
PubMed2005

Cellular mechanisms of acetaminophen: role of cyclo-oxygenase.

Acetaminophen is one of the most commonly used drugs for the safe and effective treatment of pain and fever. Acetaminophen works by lowering cyclo-oxygenase products preferentially in the central nervous system, where oxidant stress is strictly limited. However, the precise mechanism of action for acetaminophen on cyclo-oxygenase activity is debated. Two theories prevail. First, it is suggested that acetaminophen selectively inhibits a distinct form of cyclo-oxygenase, cyclo-oxygenase-3. Second, it is suggested that acetaminophen has no affinity for the active site of cyclo-oxygenase but instead blocks activity by reducing the active oxidized form of cyclo-oxygenase to an inactive form. Here, we have used an in vitro model of cyclo-oxygenase-2 activity (A549 cells stimulated with IL-1beta) to show that acetaminophen is an effective inhibitor of cyclo-oxygenase activity in intact cells. However, acetaminophen, unlike nonsteroidal anti-inflammatory drugs (NSAIDs), cannot inhibit activity in broken cell preparations. The inhibitory effects of acetaminophen were abolished by increasing intracellular oxidation conditions with the cell-permeable hydroperoxide t-butylOOH. Similarly the inhibitory effects of the cyclo-oxygenase-2 selective inhibitor rofecoxib or the mixed cyclo-oxygenase-1/cyclo-oxygenase-2 inhibitors ibuprofen and naproxen were significant reduced by t-butylOOH. By contrast, the inhibitory effects of indomethacin or diclofenac, which also inhibit both cyclo-oxygenase-1 and cyclo-oxygenase-2, were unaffected by t-butylOOH. These observations dispel the notion that cyclo-oxygenase-3 is involved in the actions of acetaminophen and provide evidence that supports the theory that acetaminophen interferes with the oxidation state of cyclo-oxygease. Moreover, they suggest for the first time that the inhibitory effects of some NSAIDs, including the newly introduced cyclo-oxygenase-2 selective inhibitor rofecoxib, owe part of their inhibitory actions to effects on oxidation state of cyclo-oxygenase. Our data with t-butylOOH and NSAIDs illustrates an, as yet, undeveloped therapeutic window for the "cyclo-oxygenase inhibitor". Specifically, combining active site selectively with actions on enzyme oxidation state would allow for a broader range of tissue selective drugs.

Acetaminophen↗
PubMed1988

Expression of heme oxygenase in hemopoiesis.

Heme oxygenase has been purified to electrophoretic homogeneity from detergent solubilized adult human liver microsomes. Treatment of microsomes with Triton X-100, sodium cholate and subsequent batchwise DEAE-cellulose, 2', 5' ADP-sepharose 4B, Sepharose CLB and hydroxylapatite column resulted in 17% yield of the purified heme oxygenase. The reconsituted system of heme oxygenase, composed of heme oxygenase, NADPH cytochrome c (P450) reductase and biliverdin reductase was equiactive with 1 mM NADPH and 4 nM NADH and showed complete dependence on added heme for catalytic activity. The Km values for NADPH and NADH were .046 and .526 mM, respectively. While NADPH concentration was held constant, the Km value for heme was 1.01 microM with a specific activity of 583 unit/mg protein. The activity of the reconstituted heme oxygenase system was not affected by preincubation with heavy metals despite their inhibitory effect of NADPH cytochrome c (P450) reductase and biliverdin reductase. However, the metalloporphyrins of these heavy metals were found to be strong inhibitors of the reconsituted system with Ki values of 0.015, 0.6, 2.3 and 5 microM for Sn-, Co-, Zn- and Mg- protoporphyrins, respectively. Similarly, the sulfhydryl inactivating reagents, HgCl2, iodoacetamide and p-chloromercurylbenzoate, inhibited the reconstituted heme oxygenase activity. Rabbits were immunized with purified human liver heme oxygenase and the resulting antibody preparation was used to examine the species specificity of the enzyme. Microsomal protein with a molecular weight of 32,000 from rat and human liver as well as HepG2 cells were identified on dot and Western blots by their reaction with the anti-heme oxygenase similar to the purified enzyme protein. Anti-heme oxygenase precipitated quantitatively, the entire heme oxygenase of rat liver microsomes obtained from animals maintained on standard diet. The human bone marrow microsomal heme oxygenase activity was also quantitatively precipitated by this antibody. Antibody inhibition of rat and human heme xoygenase demonstrated a degree of conservation of both enzyme proteins between the species. As judged by Western blotting, the anti-heme oxygenase recognized only a single protein in spleen, liver, kidney, brain, heart, bone marrow, integtine and corneal epithelium. The human heme oxygenase cDNA was isolated by screening a cDNA library in the Okayama-Berg vector with a rat liver cDNA and was subjected to nucleotide sequence analysis. The deducted human heme oxygenase is also composed of 288 amino acids with a molecular mass of 32,800 Da.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed2006

Hypoxia reduces the expression of heme oxygenase-2 in various types of human cell lines. A possible strategy for the maintenance of intracellular heme level.

Heme oxygenase consists of two structurally related isozymes, heme oxygenase-1 and and heme oxygenase-2, each of which cleaves heme to form biliverdin, iron and carbon monoxide. Expression of heme oxygenase-1 is increased or decreased depending on cellular microenvironments, whereas little is known about the regulation of heme oxygenase-2 expression. Here we show that hypoxia (1% oxygen) reduces the expression levels of heme oxygenase-2 mRNA and protein after 48 h of incubation in human cell lines, including Jurkat T-lymphocytes, YN-1 and K562 erythroleukemia, HeLa cervical cancer, and HepG2 hepatoma, as judged by northern blot and western blot analyses. In contrast, the expression level of heme oxygenase-1 mRNA varies under hypoxia, depending on the cell line; it was increased in YN-1 cells, decreased in HeLa and HepG2 cells, and remained undetectable in Jurkat and K562 cells. Moreover, heme oxygenase-1 protein was decreased in YN-1 cells under the conditions used, despite the induction of heme oxygenase-1 mRNA under hypoxia. The heme oxygenase activity was significantly decreased in YN-1, K562 and HepG2 cells after 48 h of hypoxia. To explore the mechanism for the hypoxia-mediated reduction of heme oxygenase-2 expression, we showed that hypoxia shortened the half-life of heme oxygenase-2 mRNA (from 12 h to 6 h) in YN-1 cells, without affecting the half-life of heme oxygenase-1 mRNA (9.5 h). Importantly, the heme contents were increased in YN-1, HepG2 and HeLa cells after 48 h of incubation under hypoxia. Thus, the reduced expression of heme oxygenase-2 may represent an important adaptation to hypoxia in certain cell types, which may contribute to the maintenance of the intracellular heme level.

Acclimatization↗
PubMed1983

Nickel induction of microsomal heme oxygenase activity in rodents.

Heme oxygenase activity was measured in tissues of rats killed after administration of NiCl2 or Ni3S2. Induction of renal heme oxygenase activity occurred 6 hr after NiCl2 injection (0.25 mmol/kg, sc), reached a maximum of five to six times the baseline activity at 17 hr, and remained significantly increased at 72 hr. Heme oxygenase activities were also increased in liver, lung, and brain at 17 hr after the NiCl2 injection; heme oxygenase activities in spleen and intestinal mucosa were unchanged. The effects of NiCl2 on heme oxygenase activities in kidney and liver were dose-related from 0.06 to 0.75 mmol/kg, sc. Three Ni chelators were administered (1 mmol/kg, im) prior to injection of NiCl2 (0.25 mmol/kg, sc); d-penicillamine partially prevented Ni induction of renal heme oxygenase activity; triethylenetetramine had no effect; sodium diethyldithiocarbamate enhanced the Ni induction of renal heme oxygenase activity (three times greater than NiCl2 alone). Intrarenal injection of Ni3S2 (10 mg/rat) caused induction of renal heme oxygenase activity at 1 week but not at 2, 3, or 4 weeks; no correlation was observed between induction of renal heme oxygenase activity and erythropoietin-mediated erythrocytosis. Hypoxia (10% O2, 12 hr/day, 7 days) did not affect renal heme oxygenase activity. Induction of renal heme oxygenase activity was observed in mice, hamsters, and guinea pigs killed 17 hr after injection of NiCl2 (0.25 mmol/kg, sc). These studies established (a) the time course, dose-effect, organ selectivity, and species susceptibility relationships for Ni induction of microsomal heme oxygenase activity, (b) the effects of Ni chelators, and (c) the lack of relationship between induction of renal heme oxygenase activity and the erythrocytosis that develops after intrarenal injection of Ni3S2.

Animals↗
PubMed2005

Heme oxygenase modulates small intestine leukocyte adhesion following hindlimb ischemia/reperfusion by regulating the expression of intercellular adhesion molecule-1.

OBJECTIVE: Heme oxygenase is the rate-limiting enzyme in the degradation of heme into carbon monoxide, iron, and bilirubin. Recent evidence suggests that the induction of heme oxygenase-1 is associated with potent anti-inflammatory properties. The objectives of this study were to determine the temporal, regional, and cellular distribution of heme oxygenase-1 within the small intestine and its role in modulating remote intestinal leukocyte recruitment following trauma induced by hindlimb ischemia/reperfusion. DESIGN: Randomized, controlled, prospective animal study. SETTING: Hospital surgical research laboratory. SUBJECTS: Male C57BL/6 mice. INTERVENTIONS: Mice underwent 1 hr of bilateral hindlimb ischemia, followed by 3, 6, 12, or 24 hrs of reperfusion. MEASUREMENTS AND MAIN RESULTS: Heme oxygenase-1 messenger RNA, heme oxygenase-1 protein, and heme oxygenase activity were measured using reverse transcription polymerase chain reaction, Western blot, immunohistochemistry, and spectrophotometric assay, respectively. The jejunum was also exteriorized to quantify the flux of rolling and adherent leukocytes and R-Phycoerythrin conjugated intercellular adhesion molecule-1 monoclonal antibody fluorescence intensity in submucosal postcapillary venules with the use of intravital microscopy. Ischemia/reperfusion led to a significant increase in heme oxygenase-1 messenger RNA in the jejunum and ileum 3 hrs following limb reperfusion, with a subsequent increase in heme oxygenase-1 protein and heme oxygenase activity at 6 hrs. Ischemia/reperfusion also led to a significant 1.4-fold increase in leukocyte rolling, whereas inhibition of heme oxygenase via injection of tin protoporphyrin IX (20 micromol/kg intraperitoneally) resulted in a three-fold increase in leukocyte adhesion, compared with ischemia/reperfusion alone. This increase in adhesion was significantly reduced to baseline in mice treated with intercellular adhesion molecule-1 monoclonal antibody before heme oxygenase inhibition (40 microg/mouse), whereas inhibition of heme oxygenase activity following ischemia/reperfusion also led to a significant increase in R-Phycoerythrin intercellular adhesion molecule-1 monoclonal antibody fluorescence intensity. CONCLUSIONS: Our data suggest that remote trauma induced by hindlimb ischemia/reperfusion leads to an increase in heme oxygenase activity within the small intestine, which modulates intercellular adhesion molecule-1 dependent intestinal leukocyte adhesion.

Animals↗
PubMed2000

Localization and regulation of cyclo-oxygenase-1 and -2 and neuronal nitric oxide synthase in mouse spinal cord.

Prostaglandins are important mediators in spinal nociceptive processing. They are produced by cyclo-oxygenase isoforms, cyclo-oxygenase-1 and -2, which are both constitutively expressed in the central nervous system. The present immunohistochemical study details localization and regulation of cyclo-oxygenase-1 and -2 and neuronal nitric oxide synthase in lumbar spinal cord before and after induction of a painful paw inflammation in mice. Cyclo-oxygenase-1 immunoreactivity was found in glial cells of the dorsal and ventral horns, but not in neurons. In unstimulated mice, cyclo-oxygenase-2 immunoreactivity was found in motoneurons of the ventral horns and in lamina X, but not in dorsal horn neurons. After induction of a paw inflammation with zymosan, cyclo-oxygenase-2 immunoreactivity increased dramatically in dorsal horn neurons of laminae I-VI and X, paralleled by a significant increase in prostaglandin E(2) release from lumbar spinal cord. Cyclo-oxygenase-2 was co-localized with neuronal nitric oxide synthase immunoreactivity in several neurons in superficial laminae of the dorsal horns and in the area surrounding the central canal. Nitric oxide synthase was distributed in the cytoplasm and extended to processes of some neurons. In contrast, electron microscopy revealed that cyclo-oxygenase-2 immunoreactivity was restricted to the nuclear membrane and rough endoplasmic reticulum. It is shown in the present study that both cyclo-oxygenase isoforms are constitutively expressed in the spinal cord, cyclo-oxygenase-1 in glial cells of the dorsal and ventral horns and cyclo-oxygenase-2 in motoneurons. After induction of a hindpaw inflammation, several dorsal horn neurons express cyclo-oxygenase-2. Some of them are also positive for neuronal nitric oxide synthase, which is also induced following peripheral inflammation. Intracellularly, cyclo-oxygenase-2 is bound to the membranes of the nucleus and endoplasmic reticulum, whereas neuronal nitric oxide synthase is found in the cytoplasm.

Animals↗
PubMed1999

Nitric oxide mediates the lipopolysaccharide dependent upregulation of the heme oxygenase-1 gene expression in cultured rat Kupffer cells.

BACKGROUND/AIMS: Heme oxygenase catalyzes the rate-limiting enzymatic step of heme degradation. The inducible isoform of heme oxygenase, heme oxygenase-1, is expressed at a low level in most tissues and is upregulated by its substrate heme and various stress stimuli. Kupffer cells which represent the largest population of the body's tissue macrophages serve physiological functions in the defense against various pathogens such as lipopolysaccharide. The goal of the present study was to investigate the heme oxygenase-1 gene expression in Kupffer cells of rat liver and in isolated Kupffer cell cultures during treatment with lipopolysaccharide. METHODS: Cryostat sections of normal rat liver were investigated by immunofluorescence double-staining using specific antibodies for rat heme oxygenase-1 and ED2. Isolation and cell culture of Kupffer cells and primary hepatocytes from rat liver, as well as Northern and Western blot analysis, were performed with standard protocols. RESULTS: Heme oxygenase-1 protein was highly expressed in large sinusoidal cells of normal rat liver, which were identified as Kupffer cells by staining with the macrophage surface marker ED2. By contrast, no expression of heme oxygenase-1 was detected in liver parenchymal cells. High expression of heme oxygenase-1 was also found in isolated Kupffer cells in culture by immunocytochemical staining as well as by Western and Northern blot analysis. After treatment of Kupffer cells cultures with lipopolysaccharide, heme oxygenase-1 was upregulated on the protein and mRNA level in a time- and dose-dependent manner. This increase in heme oxygenase-1 expression by lipopolysaccharide was prevented by the nitric oxide inhibitor N(G)-monomethyl-L-arginine which was reversed by an excess of L-arginine. Various nitric oxide donors up-regulated heme oxygenase-1 mRNA expression in Kupffer cells. CONCLUSIONS: The lipopolysaccharide-dependent upregulation of the heme oxygenase-1 gene which is highly expressed in Kupffer cells is mediated by a nitric oxide-dependent mechanism.

Animals↗
PubMed2004

Heme oxygenase-1 messenger RNA expression is induced in peripheral blood mononuclear cells of pediatric cancer patients with systemic inflammatory response syndrome.

OBJECTIVE: To determine whether heme oxygenase-1 messenger RNA expression in peripheral blood mononuclear cells is induced in pediatric cancer patients with the systemic inflammatory response syndrome (SIRS) and whether this expression correlates with the heme oxygenase-1 products, bilirubin and carboxyhemoglobin. DESIGN: Prospective, controlled study. SETTING: A tertiary care pediatric oncology hospital. PATIENTS: Fourteen patients admitted to the intensive care unit with a diagnosis of SIRS by American College of Chest Physicians/Society for Critical Care Medicine consensus criteria and 17 control patients (off therapy, no acute illness). INTERVENTIONS: Blood for bilirubin, carboxyhemoglobin, and heme oxygenase-1 messenger RNA expression was collected at study entry. SIRS patients continued to have samples collected every 12 hrs for 1 wk or until intensive care unit discharge. Heme oxygenase-1, bilirubin, and carboxyhemoglobin levels of SIRS patients were compared with controls, and correlation between heme oxygenase-1 and products was assessed. MEASUREMENTS AND MAIN RESULTS: Within 48 hrs of study entry, maximum heme oxygenase-1 expression for all SIRS patients compared with controls was 5.5 +/- 1.0 vs. 1.1 +/- 0.1 (p < .0006). Maximum expression was > or =2.3-fold in 13 of 14 SIRS patients. Maximum heme oxygenase-1 expression also differed from minimum (5.5 +/- 1.0 vs. 1.6 +/- 0.3, p < .003). Maximum bilirubin and carboxyhemoglobin levels within 48 hrs of study entry differed between SIRS patients and controls (3.0 +/- 0.8 vs. 0.3 +/- 0.1, p = .006; and 1.2 +/- 0.2 vs. 0.6 +/- 0.1, p = .001, respectively). Bilirubin, but not carboxyhemoglobin, correlated with heme oxygenase-1 expression (p = .0013). CONCLUSIONS: Heme oxygenase-1 messenger RNA, bilirubin, and carboxyhemoglobin levels were increased within 48 hrs of admission in pediatric cancer patients with SIRS. Heme oxygenase-1 expression correlated with serum bilirubin levels. The increase in heme oxygenase-1 expression may add to the understanding of the increase in serum bilirubin observed in patients with SIRS/sepsis. These findings support a role for heme oxygenase-1 in the physiologic response to inflammatory stress.

Adolescent↗
PubMed1990

Developmental biology of heme oxygenase.

The regulation of heme oxygenase activity in the developing neonate is essential to the control of bilirubin production as well as intracellular heme and hemoprotein metabolism. The coordinated activity of the microsomal enzymes, heme oxygenase and NADPH-cytochrome c (P450) reductase, and the cytosolic enzyme biliverdin reductase is responsible for the degradation of heme. The complete reaction sequence requires oxygen and NADPH, and produces bilirubin and carbon monoxide in equimolar amounts. Although heme oxygenase expresses a rather broad range of substrate affinities, the oxidative degradation of heme is exclusively alpha-specific. Heme oxygenase is found in several tissues, with significant activity levels in the liver, spleen, and erythropoeitic tissue. Heme oxygenase activity is inducible by heme and other metalloporphyrins, hormones, starvation, stress, toxins, and xenobiotics. Heme oxygenase induction is generally considered to be the result of an increased protein synthesis and gene transcription. This hypothesis is supported by recent studies of the heme oxygenase gene that identified inducer element binding sites responsive to metal administration, heat shock, and nutrient availability. In the developing fetus and neonate, hepatic heme oxygenase activity and mRNA levels are elevated above that of the adult. This suggests that the elevated heme catabolism observed in neonates may be associated with an increased transcription of the heme oxygenase gene. The apparent induction of hepatic heme oxygenase during the neonatal period is probably the result of tissue-specific and time-dependent transcriptional regulating factors including potentially hormones and heme. Several metalloporphyrins, such as the tin and zinc porphyrin complexes, inhibit heme oxygenase activity and thus have therapeutic potential for the treatment of neonatal jaundice. Recent studies suggest that the meso- and bis-glycol derivatives of these metalloporphyrins may be more potent inhibitors of heme oxygenase activity in vitro and in vivo than the protoporphyrin structures. As structural analogues of heme, however, these compounds may also have other less desirable effects on the regulation of heme and hemoprotein metabolism, particularly in the developing neonate.

Chemical Phenomena↗