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Neonatal hyperbilirubinemia results from a readiness for the bilirubin production in neonates and limited their ability to excrete it. The diagnosis of hyperbilirubinemia based on yellow discoloration of the skin and whiteness of eyes, idle in the child's movement and the lack of lactation. The baby seems sick or is difficult to awaken. Bilirubin is a tetrapyrrole pigment derived from breakdown product of normal heme catabolism in senescent red blood cells. Unconjugated bilirubin normal elevation is named newborn physiologic hyperbilirubinemia, whereas the level of bilirubin of infant normally to be a bit higher after birth, In the same context the placenta in the womb of the mother. Pathologic hyperbilirubinemia is defined as odd of bilirubin from the normal level so intervention required. Many reasons for this type of jaundice

Heme catabolism is an important physiological process that converts heme to biliverdin in the presence of heme oxygenase which has an essential role in destroying unwanted heme. Verdohemes, the green iron (II) complexes of the 5-oxaporphyrin macrocycle are produced by oxidative destruction of heme. The main goal of this study is clarification of the central metal effect on stabilization of metal 5-oxaporphyrin molecules. To investigate the role of central metal on geometric and electronic properties of five coordinated verdoheme analogues, the first row transitional metals, including Sc, Ti, V, Cr, Mn, Fe, Co, Ni, Cu and Zn, as the central metal of five-coordinated metal 5-oxaporphyrins were systematically calculated without any symmetry constraint by using the B3LYP as DFT method and the 6-31G basis set in gas and solvent phases. According to the results, the stabilization energy of metal 5-oxaporphyrins increases with atomic mass in the solvent phase more than in the gas phase. By reviewing the properties such as the computed frontier orbital energy, HOMO and LUMO gap energy [Formula: see text], hardness [Formula: see text], chemical potential [Formula: see text], softness (s) and electrophilicity [Formula: see text], the pharmaceutical use of this compound can be discussed.

Bile is composed of multiple macromolecules, including bile acids, free cholesterol, phospholipids, bilirubin, and inorganic ions that aid in digestion, nutrient absorption, and disposal of the insoluble products of heme catabolism. The synthesis and release of bile acids is tightly controlled and dependent on feedback mechanisms that regulate enterohepatic circulation. Alterations in bile composition, impaired gallbladder relaxation, and accelerated nucleation are the principal mechanisms leading to biliary stone formation. Various physiologic conditions and disease states alter bile composition and metabolism, thus increasing the risk of developing gallstones.

Recent research on bilirubin, a historically well-known waste product of heme catabolism, suggests an entirely new function as a metabolic hormone that drives gene transcription by nuclear receptors. Studies are now revealing that low plasma bilirubin levels, defined as “hypobilirubinemia,” are a possible new pathology analogous to the other end of the spectrum of extreme hyperbilirubinemia seen in patients with jaundice and liver dysfunction. Hypobilirubinemia is most commonly seen in patients with metabolic dysfunction, which may lead to cardiovascular complications and possibly stroke. We address the clinical significance of low bilirubin levels. A better understanding of bilirubin’s hormonal function may explain why hypobilirubinemia might be deleterious. We present mechanisms by which bilirubin may be protective at mildly elevated levels and research directions that could generate treatment possibilities for patients with hypobilirubinemia, such as targeting of pathways that regulate its production or turnover or the newly designed bilirubin nanoparticles. Our review here calls for a shift in the perspective of an old molecule that could benefit millions of patients with hypobilirubinemia.

We measured end-tidal CO levels in 50 jaundiced newborns readmitted for phototherapy at age 54-244 hours. The median end-tidal CO level was 1.55 ppm, suggesting that hemolysis is not the primary contributor to the hyperbilirubinemia in many readmitted newborns.

Heme oxygenase (HO) enzymes are involved in heme catabolism and several physiological functions. Among the different HO isoforms, HO-2 stands out for its neuroprotective properties and modulatory activity in male reproduction. However, unlike the HO-1 ligands, the potential therapeutic applications of HO-2 inhibitors/activators have not been extensively explored yet. Moreover, the physiological role of HO-2 is still unclear, mostly due to the lack of highly selective HO-2 chemical probes. To boost the interest on this intriguing target, the present review updates the knowledge on the structure-activity relationships of HO-2 inhibitors and activators, as well as their potential therapeutic applications. To the best of our knowledge, among HO-2 inhibitors, clemizole derivatives are the most selective HO-2 inhibitors reported so far (IC50 HO-1 >100 μM, IC50 HO-2 = 3.4 μM), while the HO-2 nonselective inhibitors described herein possess IC50 HO-2 values ≤ 10 μM. Furthermore, the development of HO-2 activators, such as menadione analogues, helped to understand the critical moieties required for HO-2 activation. Recent advances in the potential therapeutic applications of HO-2 inhibitors/activators cover the fields of neurodegenerative, cardiovascular, inflammatory, and reproductive diseases further stimulating the interest towards this target.

Intracerebral hemorrhage (ICH) is a fatal acute cerebrovascular disease, with a high morbidity and mortality. Following ICH, erythrocytes release heme and several of its metabolites, thereby contributing to brain edema and secondary brain damage. Heme oxygenase is the initial and rate-limiting enzyme of heme catabolism, and the expression of heme oxygenase-1 (HO-1) is rapidly induced following acute brain injury. As HO-1 exerts it effects via various metabolites, its role during ICH remains complex. Therefore, in-depth studies regarding the role of HO-1 in secondary brain damage following ICH may provide a theoretical basis for neuroprotective function after ICH. The present review aims to summarize recent key studies regarding the effects of HO-1 following ICH, as well as its influence on ICH prognosis.

Background: Glucose-6-phosphate dehydrogenase (G6PD) deficiency is a common enzyme deficiency affecting more than 300 million individuals worldwide. Extreme neonatal hyperbilirubinemia, with its severe sequelae of bilirubin neurotoxicity and the potential of death, is the most devastating manifestation of G6PD deficiency. In a recent review of Favism, Luzzatto and Arese state that the pathophysiology of jaundice in G6PD-deficient neonates is different from that of favism, as there is little evidence of hemolysis in these infants. Objectives: To explore the role of hemolysis in neonatal hyperbilirubinemia associated with G6PD deficiency. Methods: Previously published works including studies of endogenous production of carbon monoxide (CO), an index of heme catabolism, in hyperbilirubinemic G6PD-deficient neonates were reviewed to determine the role of hemolysis in this condition. Results: Three studies demonstrated that endogenous CO production is elevated in G6PD-deficient neonates with extreme hyperbilirubinemia. Conclusions: Hemolysis is an important pathogenetic factor in G6PD deficiency-associated neonatal hyperbilirubinemia.

Carbon monoxide (CO) production from heme catabolism is increased with hemolysis. A portable end-tidal CO (ETCO) monitor was used to analyze breath samples in 16 children with sickle cell anemia (SCA, 5-14 years). Median (range) ETCO for SCA was 4.35 ppm (1.8-9.7) versus 0.80 ppm (0.2-2.3) for controls (P 2.1 ppm provided sensitivity and specificity of 93.8% (69.8-99.8%) for detecting SCA. ETCO correlated with reticulocytosis (P = 0.015) and bilirubin (P = 0.009), and was 32% lower in children receiving hydroxyurea (P = 0.09). Point-of-care ETCO analysis may prove useful for non-invasive monitoring of hemolysis and as a screening test for SCA.

Because heme catabolism leads to the formation of equimolar amounts of carbon monoxide (CO) and bilirubin, a variety of techniques have been developed to correlate CO production rates as indices of bilirubin production. The use of end-tidal breath CO measurements for estimating rates of bilirubin production in infants has been well documented and validated in a number of clinical studies for its use and predictive value in identifying infants who are high producers of bilirubin and hence at risk for developing pathologic neonatal hyperbilirubinemia. Recently, end-tidal breath CO has been suggested as a marker for chronic lung disease and developmental problems. Trace gas analysis remains an area for interesting investigation in the future.

Carbon monoxide production (VCO) total body heme (TBH) and serum bilirubin (SB) have been determined in healthy young men before and after 100 mg phenobarbital (10 subjects), 15 mg diazepam (7 subjects) and 75 mg oxazepam (7 subjects), respectively, daily for seven days. None of the drugs had any significant effect on VCO. SB and TBH were also unaffected. Baseline VCO (mean +/- 1 S.E.M.) was 12.6+/-0.6 mumol/mmol TBH and day. The postdrug VCO was 15.1+/-1.8, 14.1+/-1.4 and 14.7+/-1.5 after phenobarbital, diazepam and oxazepam, respectively. The corresponding values for SB were 5.4+/-0.8, 6.0+/-1.5 and 6.2+/-1.0 mug/ml, compared to a baseline value of 6.6+/-0.8 mug/ml. However, when the pooled postdrug data were compared with the pooled baseline values, mean VCO showed a probably significant increase (from 12.6+/-0.6 to 14.7+/-1.0 mumol/mmol TBH and day (p less than 0.05). It is concluded that although phenobarbital is known to increase the hepatic heme turnover, this effect is not measurable in terms of total heme turnover, no more than 20% of which comes from the liver.

As a by-product of heme catabolism by the heme oxygenase system, carbon monoxide (CO) has been neglected for many years, and only recently has its role as an essential signaling molecule been appreciated. In the past decade, the use of CO gas in pre-clinical experimental models of disease has produced some remarkable data indicating that its therapeutic delivery to mammals could alleviate inflammatory processes and cardiovascular disorders. However, the inherent toxic nature of CO cannot be ignored, knowing that inhalation of uncontrolled amounts of this gas can ultimately lead to serious systemic complications and neuronal derangements. From a clinical perspective, a key question is whether a safe and therapeutically effective threshold of CO can be reached locally in organs and tissues without delivering potentially toxic amounts through the lung. The advent of CO-releasing molecules (CO-RMs), a group of compounds capable of carrying and liberating controlled quantities of CO in cellular systems, appears a plausible alternative in the attempt to overcome the limitations of CO gas. Although in its infancy and far from being used for clinical applications, the CO-RMs technology is supported by very encouraging biological results and reflected by the chemical versatility of these compounds and their endless potential to be transformed into CO-based pharmaceuticals.

Fetal liver immaturity is accompanied by active heme catabolism. Thus fetal biliary pigments must be excreted toward the mother by the placenta. To investigate biliverdin handling by the placenta-maternal liver tandem, biliverdin-IXα was administered to 21-day pregnant rats through the jugular vein or the umbilical artery of an in situ perfused placenta. Jugular administration resulted in the secretion into maternal bile of both bilirubin and biliverdin (3:1). However, when biliverdin was administered to the placenta, most of it was transformed into bilirubin before being transferred to the maternal blood. Injecting Xenopus laevis oocytes with mRNA from rat liver or placenta enhanced their ability to take up biliverdin, which was inhibited by estradiol 17β-d-glucuronide. The expression of three OATP isoforms in this system revealed that they have a varying degrees of ability to transport biliverdin (Oatp1/1a1 > Oatp2/1a4 > Oatp4/1b2). The abundance of their mRNA in rat trophoblast was Oatp1/1a1 >> Oatp4/1b2 > Oatp2/1a4. The expression of biliverdin-IXα reductase in rat placenta was detected by RT-PCR/sequencing and Western blot analysis. The relative abundance of biliverdin-IXα reductase mRNA (determined by real-time quantitative RT-PCR) was fetal liver > placenta > maternal liver. Common bile duct ligation in the last week of pregnancy induced an upregulation of biliverdin-IXα reductase in maternal liver but had no effect on fetal liver and placenta. In conclusion, several members of the OATP family may contribute to the uptake of fetal biliverdin by the rat placenta. Before being transferred to the mother, biliverdin is extensively converted into bilirubin by biliverdin-IXα reductase, whose expression is maintained even though bilirubin excretion into maternal bile is impaired.

It has been reported that exhaled carbon monoxide (CO) concentrations and arterial carboxyhemoglobin (CO-Hb) concentration in blood may be increased in critically ill patients. However, there was no study that examined correlation among amount of CO in exhaled air, CO-Hb concentrations in erythrocytes, and bilirubin IXα (BR) in serum, i.e., the three major indexes of heme catabolism, within the same subject. Here, we examined CO concentrations in exhaled air, CO-Hb concentrations in arterial blood, and BR levels in serum in 29 critically ill patients. Measurements of exhaled CO, arterial CO-Hb, and serum total BR have been done in the intensive care unit. As control, exhaled CO concentration was also measured in eight healthy volunteers. A median exhaled CO concentration was significantly higher in critically ill patients compared with control. There was significant correlation between CO and CO-Hb and CO and total BR level. We also found CO concentrations correlated with indirect BR but not direct BR. Multivariate linear regression analysis for amount of exhaled CO concentrations also showed significant correlation with CO-Hb and total BR, despite the fact that respiratory variables of study subjects were markedly heterogeneous. We found no correlation among exhaled CO, patients’ severity, and degree of inflammation, but we found a strong trend of a higher exhaled CO concentration in survivors than in nonsurvivors. These findings suggest there is an increased heme breakdown in critically ill patients and that exhaled CO concentration, arterial CO-Hb, and serum total BR concentrations may be useful markers in critically ill conditions.

Aim Accurate measurement of Hb saturation is essential in the care of children with sickle cell disease (SCD). The gold standard of Hb saturation measurement is by ABG with co-oximetry. Minute-by-minute changes are detected with pulse oximetry (SpO2). SpO2 shows good correlation to ABG co-oximetry in well patients with normal Hb. SCD patients represent a different population: previous small studies have shown discrepancies in calculated ABG and SpO2 Hb saturations. SpO2 may be falsely low due to high carboxyhaemoglobin and metahaemaglobin levels following heme catabolism, or high due to hyperbilirubinaemia. Both occur in acute and chronic haemolysis. With treatment decisions in acute and ambulatory settings driven by bedside SpO2, inaccuracies can result in mismanagement. Earlobe blood gas (EBG) co-oximetry is an alternative better tolerated method of measuring Hb O2 saturation in arterialised capillary blood (SaO2), with good correlation to ABG measurements. We sought to investigate the correlation between SpO2 and SaO2 measured by EBG co-oximetry in ambulatory SCD children. Methods We retrospectively reviewed paediatric SCD patients attending a UK tertiary sickle-respiratory clinic from February 2012–August 2015, and who had simultaneous EBG and SpO2 measurements. Positive difference results from SpO2 value greater than EBG SaO2. Results We identified 39 simultaneous paired SaO2 and SpO2 readings from 33 patients (52% male, median age 10years, range: 5–17). Mean difference between readings was –0.7% (Figure 1 and 2). In 23% of cases, difference was >±2%. SaO2 was overestimated in one-third and underestimated in two-thirds. Of 17 hypoxaemic measurements (SpO2 Conclusion Pulse oximetry as a measure of Hb oxygen saturation was inaccurate in a significant proportion of ambulatory SCD children. SpO2 tended to be lower than actual SaO2 as measured with EBG, with SpO2≥94% more likely to predict true result than SpO2

Bilirubin was long considered a useless metabolite of heme catabolism, responsible for the clinical manifestation of jaundice, and potentially toxic in high doses, particularly in neonates. In the past two decades the potent biological properties of bilirubin, particularly as an antioxidant, have been recognised, and this has prompted a number of investigations into this molecule concerning its in vitro and in vivo properties. This review summarises that work, as well as more recent investigations into the potential therapeutic uses of bilirubin.

Heme, an iron-porphyrin complex, is the prosthetic group of hemoglobin, myoglobin, cytochromes, and many other proteins. Iron is required for the biosynthesis of heme and other non-heme iron containing proteins. Several specific proteins participate in the orchestration of iron metabolism. Iron metabolism consists of the absorption of dietary iron from the gastrointestinal tract, transport in the blood, storage in the liver and macrophages, and utilization in the cells requiring synthesis of iron-containing proteins. Iron deficiency causes anemia and iron excess causes iron accumulation diseases known as hemochromatosis. Ferrous iron is absorbed principally from the mature enterocytes lining the absorptive villi of the duodenum. At the apical membrane of the enterocyte, Fe 3+ is converted to Fe 2+ by ferrireductase followed by its uptake mediated by divalent transporter 1 (DMT1). The internalized Fe 2+ is either temporarily stored after conversion to Fe 3+ as ferritin, or transported across the cell for transport to the portal capillary blood circulation

Carbon monoxide is produced endogenously in humans through the breakdown of hemoglobin by heme oxygenase. Although originally thought to be a superfluous by-product of heme catabolism, carbon monoxide is now known to play a central role in many aspects of human health and disease. The functions of carbon monoxide that have been described to date are myriad, including blood pressure regulation, maintenance of organ-specific vascular tone, neurotransmission, stress response, platelet activation, and smooth muscle relaxation. This review outlines what is known to date about carbon monoxide as it relates to human disease.

Bilirubin, the end product of heme catabolism in mammals, is generally regarded as a potentially cytotoxic, lipid-soluble waste product that needs to be excreted. However, in the last 10 years, in vitro and in vivo studies, have demonstrated that bilirubin exhibits potent anti-oxidant properties preventing the oxidative damage triggered by a wide range of oxidant-related stimuli. Therefore, the idea of a beneficial and physiological role for bilirubin in cytoprotection against short and long-lasting oxidant-mediated cell injury is highlighted here.

Submitted by Boris INFORMAT (boris@uerj.br) on 2021-04-26T01:11:19Z No. of bitstreams: 1 Mauricio Cupello Peixoto Tese completa.pdf: 4602090 bytes, checksum: b6f6bb8553f6f8cd926d3c4c1197e091 (MD5) Made available in DSpace on 2021-04-26T01:11:19Z (GMT). No. of bitstreams: 1 Mauricio Cupello Peixoto Tese completa.pdf: 4602090 bytes, checksum: b6f6bb8553f6f8cd926d3c4c1197e091 (MD5) Previous issue date: 2014-09-19 Trypanosoma cruzi, the causal agent of Chagas disease, has a complex life cycle and they must cope with diverse environmental conditions and depends on hosts for its nutritional needs. One of the nutritional characteristic is that they need a heme compound (Fe-protoporphyrin IX) as a growth factor. The mechanisms involved in these processes are crucial for their survival mainly because of trypanosomatids lack of the complete heme biosynthetic pathway and the cytotoxic activity of free heme. Following the fate of this porphyrin in the parasite we studied this missing pathway in T. cruzi. Here, we show that epimastigotes cultivated with heme yielded the compounds, α-meso hydroxyheme, verdoheme and biliverdin (as determined by HPLC with diode array detector). Furthermore, we observed ion species of m/z 583.4 and m/z 619.3 from epimastigotes extracts detected by direct infusion on LQT Orbitrap platform. A tipical biliverdin and verdoheme doughter-ion species were generated by m/z 583.4 and m/z 619.3 fragmentations, respectively. We also observed an ion species at m/z 1397.4 and m/z 1135. The subsequent fragmentation of this species produced a daughter-ions whose one with the same molecular mass as heme (m/z 616.4). This species, in turn, generated daughter species identical to an authentic heme, confirming that these intermediates were modified heme products. Based on these findings, we propose that heme catabolism in T. cruzi involves a additions of Bis(glutathionyl)spermine, a low molecular mass thiols occurring in trypanosomatids, to heme (m/z 1397.4), followed by removal of the glutamic residues (m/z 1135). Although the biochemical and physiological significance of the addition of thiol residues to heme molecule is underexplored, some works, already demonstrated their ability to bind heme and also this modified heme may resulting in the effective prevention of membrane damage and cytotoxicity by the heme accumulation. Taken together, these results offer new insights into heme metabolism in T. cruzi, revealing potential future therapeutic targets. We propose an active heme catabolism pathway that includes a trypanotione derivate additions and cleavage of the heme porphyring ring to biliverdin. O Trypanosoma cruzi, agente etiológico da doença de Chagas, possui um ciclo de vida complexo, deve lidar com diversas condições do ambiente e depende dos hospedeiros para suprir suas necessidades nutricionais. Uma delas é a necessidade de captar a molécula de heme (Fe-protoporfirina IX) que será utilizada como fator de crescimento. Os mecanismos envolvendo o metabolismo de heme são cruciais para a sobrevivência do T. cruzi pois o parasito não possui várias enzimas de biossíntese dessa porfirina e o heme livre pode apresentar citotoxicidade para célula. Na tentativa de perseguir o destino final do heme no parasito, nós estudamos essa via inexplorada no T. cruzi. Nessa tese, nós demonstramos que epimastigotas cultivados com heme, produziram os compostos, α-meso hidroxiheme, verdoheme e biliverdina (identificados por HPLC acoplado á espectrofotômetria). Além disso, nós observamos através de análise dos extratos de epimastigotas no espectrômetro de massas (LQT Orbitrap), espécies iônicas de m/z 583,4 e m/z 619,3. A fragmentação subsequente desses íons originaram espécies filhas típicas das moléculas de biliverdina e verdoheme, respectivamente. Nós observamos também, espécies iônicas de m/z 1397,4 e m/z 1135,4. A fragmentação dessas espécies produziram íons, sendo um deles com a mesma massa molecular de heme (m/z 616,3). Essa espécie iônica por sua vez, gerou fragmentos iônicos idênticos a uma molécula de heme, confirmando que esses intermediários são produtos da modificação da porfirina. Baseado nesses resultados, nós propomos um modelo onde o catabolismo de heme em T. cruzi, envolveria a conjugação da bis(glutationil)spermina, um derivado da tripanotiona presente em tripanossomatídeos, à porfirina (m/z 1137,4), seguido da remoção de dois resíduos de ácidos glutâmicos (m/z 1135,4). Embora o significado bioquímico e fisiológico da adição desse resíduo tiol na molécula de heme ainda é pouco compreendido, alguns trabalhos demonstram a abilidade desses compostos em ligar na porfirina, sem contar também, que esse heme conjugado poderia resultar em uma forma efetiva de prevenção de danos à membrana e a célula ocasionados pelo acúmulo de heme livre. Em conjunto, esses resultados fornecem novas abordagens do metabolismo de heme em T. cruzi, revelando possíveis alvos de intervenção quimioterápica futuros. Nossa proposta está direcionada para uma via ativa de catabolismo de heme que inclui a adição de grupos tiol (derivado da tripanotiona) à heme e a clivagem do anel porfirínico originando a molécula de biliverdina.

Low concentrations of endogenous carbon monoxide (CO), generated through catabolism of heme-proteins, have been shown to protect tissues against inflammatory diseases, and ischemia-reperfusion injuries. However, elevated carboxyhemoglobin (COHb) formed by CO binding to hemoglobin, prevents adequate O2 delivery to tissues by lowering arterial O2 content. Therefore there must be a balance in the level of endogenous CO which maximizes cytoprotective effects and minimizes inhibition of O2 delivery. The elevated heme-protein concentrations as found in marine mammals, are likely associated with increased heme catabolism, and subsequently increased endogenous CO production and COHb values. We measured COHb in elephant seals, a species with exceptional blood volumes, hemoglobin concentrations and myoglobin content. The mean value in adult seals was 8.7 ± 0.3%, while juveniles and pups (with lower heme-protein stores) had COHb values of 7.6 ± 0.2% and 7.1 ± 0.3%, respectively. Serial samples over several hours rev...

Bilirubin is a product of heme catabolism which by virtue of its lipid solubility can cross the blood-brain barrier and enter the brain. Neonatal jaundice is a common transitional phenomenon which is due to the combination of increased heme catabolism and rate limitations as far as hepatic conjugation and biliary excretion of bilirubin. In the great majority of cases this is an innocuous condition, which is even posited to have some beneficial effects due to the ability of bilirubin to quench free oxygen radicals. However, because bilirubin is neurotoxic, hyperbilirubinemia in the newborn may exceptionally result in death in the neonatal period, or survival with severe neurological sequelae (kernicterus). Bilirubin enters the brain through an intact blood-brain barrier. Clearance of bilirubin from brain partly involves retro-transfer through the blood-brain barrier, and possibly also through the brain-CSF barrier into CSF. Work in our lab during the past 5 years has substantiated earlier work which had suggested that bilirubin may also be metabolized in brain. The responsible enzyme is found on the inner mitochondrial membrane, and oxidizes bilirubin at a rate of 100-300 pmol bilirubin/mg protein/minute. The enzyme activity is lower in the newborn compared with the mature animal, and is also lower in neurons compared with glia. Studies of different rat strains have documented genetic variability. The enzyme is cytochrome-c-dependent, but has as yet not been unequivocally identified. The rate of oxidation of bilirubin is such that this enzyme probably contributes meaningfully to the clearance of bilirubin from brain.

Heme oxygenase-1 (HO-1) catalyzes the rate-limiting step in heme catabolism and presumably is involved in cellular iron homeostasis. It is induced by a variety of cellular stresses, including oxygen deprivation and free radical-mediated stress. We examined induction of HO-1 mRNA in skin fibroblasts and investigated the mechanism by which it occurs. Hypoxia did not appear to act via induction of oxygen free radicals: induction of HO-1 was not sensitive to the free radical scavenger GSH or other antioxidants. Moreover, hypoxia did not increase steady-state levels of free radicals generated by fibroblasts. In contrast, HO-1 induction by the oxidants, H2O2and carbonyl cyanide m-chlorophenylhydrazone (CCCP) was significantly attenuated in the presence of free radical scavengers. This correlated with increased levels of free radical production in fibroblasts treated with these oxidants. Iron depletion by desferrioxamine mesylate, a specific iron complexon, completely inhibited hypoxic stimulation of HO-1 but did not attenuate the effect of H2O2and CCCP on HO-1 mRNA. Addition of Fe2+, Fe3+, or holo-transferrin to fibroblasts increased levels of HO-1 mRNA. Treatment of cells with hypoxia, but not H2O2or an exogenous source of iron, significantly increased the half-life of HO-1 mRNA. The data suggest hypoxia regulates HO-1 gene expression by a specific posttranscriptional mechanism: stabilization of mRNA. Hypoxia has previously been shown to increase fibroblast collagen synthesis and is thought to play a role in pathogenesis of systemic sclerosis (SSc). Skin fibroblasts isolated from patients with SSc demonstrated significantly stronger induction of HO-1 by hypoxia than did fibroblasts from normal controls. We hypothesize that exposure of SSc fibroblasts to hypoxic conditions leads to in vivo selective proliferation of cells that adapt to hypoxia.

Several β-aryl and heteroarylpyrroles have been synthesized by palladium-catalyzed coupling reaction of β-tributylstannylpyrroles with aryl and heteroaryl halides in 62–89% yields. These precursors may be readily converted into β-aryl and heteroaryl substituted porphyrins for the study of the oxophlorin to oxaporphyrin conversion in heme catabolism, catalyzed by heme oxygenase.

The production of bilirubin from heme degradation can be an important cause of neonatal hyperbilirubinemia in a certain subpopulation. Measurements of carbon monoxide production can be used as an index of heme catabolism and bilirubin production. This process can be inhibited by synthetic metalloporphyrin analogs of heme. This review focuses on approaches to identify those neonates who have increased total bilirubin production and to explore some of the new developments in therapeutic modalities.

CO is a tasteless, odorless and colorless gas. The existence of endogenous CO in the human body arises from heme catabolism (Meredith and Vale 1988; Ernst and Zibrak 1998) and oxidation of organic molecules (Marilena 1997). Endogenous CO acts as a neurotransmitter for long-term potentiation, consequently playing a key role in memory and learning (Marilena 1997). It also plays a role in modulating inflammation, apoptosis, cell proliferation, mitochondrial biogenesis (Weaver 2009) and vascular relaxation (Marilena 1997). Exogenous sources of CO intoxication include smoking, forest fires, pollutants, and improper usage of heaters or furnaces (Weaver 2009; Kumar, Prakash et al. 2010). CO intoxication usually indicates exposure to exogenous sources and is considered one of the most common causes of poisoning worldwide (Prockop and Chichkova 2007; Weaver 2009), with 1000 deaths annually in Britain (Meredith and Vale 1988), and 4000-6000 deaths annually in the United States (Tibbles and Perrotta 1994; Ernst and Zibrak 1998; Weaver 1999). In Asia, the exact epidemiology remains unclear. In Japan, Hong Kong and Taiwan, a common CO etiology of intoxication is charcoal burning suicide (Lee, Chan et al. 2002). In Japan, poisoning by charcoal burning is the most lethal form of suicide and is a highly prevalent method among men aged 25-64 years of age (Kamizato, Yoshitome et al. 2009), in contrast to a high rate of drug poisoning as a method of suicide in women. In Hong Kong, the risk factors of suicide by charcoal burning are male and living alone with financial stress (Lee and Leung 2009). In Taiwan, charcoal burning was not a common method of suicide before 1998, with a rate of only 0.14 per 105 people per year (Lin and Lu 2008). With the dissemination of media and the internet, the rate of charcoal burning suicides dramatically increased by 40-fold, reaching a rate of 5.38 per 105 people per year in 2005 (Lin and Lu 2008).

In this issue of Blood, Garcia-Santos et al advance the field of heme regulation, a highly complex process involving iron and globin metabolism. They focus on a key enzyme involved in heme catabolism, heme oxygenase 1 (HO-1), which, ironically, has been poorly investigated in erythroid cells, the largest pool of heme-containing cells.

Until recently, carbon monoxide (CO) was thought of a toxic gaseous waste product of heme catabolism. Although recent evidence following left anterior descending artery (LAD) ligation in rats has suggested a potential cardioprotective effect of low dose inhaled CO, the molecular mechanism underlying this protection are obscure. The purpose of this study was to elucidate the mechanistic basis for this effect. Myocardial ischemia-reperfusion injury (LAD ligation) was performed in mice which were exposed to room air (RA) or low dose CO (250 ppm) 24 hrs before ischemia. Myocardial infarct size was significantly diminished (by 38%; p

Iron is a critical micronutrient, and iron derived from heme contributes a large proportion of the total iron absorbed in a typical Western diet. Heme iron is absorbed by different mechanisms than non-heme iron, but despite considerable study over many years these mechanisms remain poorly understood. This review provides an overview of the importance of heme iron in the diet and discusses the two prevailing hypotheses of heme absorption; namely receptor mediated endocytosis of heme, and direct transport into the intestinal enterocyte by recently discovered heme transporters. A specific emphasis is placed on the questions surrounding the site of heme catabolism and the identity of the enzyme that performs this task. Additionally, we present the hypothesis that a non-heme iron transport protein may be required for heme iron absorption and discuss the experiences of our laboratory in examining this hypothesis.

A portable, prototype instrument that measures peak CO, CO2 and H2 concentrations of breath samples was evaluated on 58 antibody positive, blood group incompatible infants. The reproducibility of 108 duplicate breath CO determinations improved when the result was normalized (CO(n)) for the simultaneously measured CO2 concentration (r = 0.97 versus r = 0.87). The average CO(n) for 18 antibody positive, ABO incompatible infants who received phototherapy was 1.2 ppm higher than the average for 32 who did not receive phototherapy (p0.001). There was a positive correlation between CO(n) and the duration of phototherapy (r = 0.75). Sodium acetate infusion and breath H2 did not affect the CO(n) results. In antibody positive infants, single breath CO to CO2 ratios provided more reproducible results than CO determinations that were not adjusted for the CO2 concentration. Therefore, a portable instrument that measures both gases on the same aliquot of exhaled air and that is not affected by H2 should have clinical utility as an indicator of heme catabolism and bilirubin production that is not distorted by hyper- or hypoventilation.

Bilirubin, the principal bile pigment, is the end product of heme catabolism. For many years, bilirubin was thought to have no physiological function other than that of a waste product of heme catabolism--useless at best and toxic at worst. Although hyperbilirubinemia in neonates has been shown to be neurotoxic, studies performed during the past decade have found that bilirubin has a number of new and interesting biochemical and biological properties. In addition, there is now a strong body of evidence suggesting that bilirubin may have a beneficial role in preventing oxidative changes in a number of diseases including atherosclerosis and cancer, as well as a number of inflammatory, autoimmune, and degenerative diseases. The results also suggest that activation of the heme oxygenase and heme catabolic pathway may have beneficiary effects on disease prevention either through the action of bilirubin or in conjunction with bilirubin. If so, it may be possible to therapeutically induce heme oxygenase, increase bilirubin concentrations, and lower the risk of oxidative stress-related diseases.

OBJECTIVE. Neonatal jaundice is the result of an imbalance between bilirubin production and elimination, and our objective was to clarify the contribution of an increase in bilirubin production to hyperbilirubinemia in newborns.METHODS. We measured the end-tidal carbon monoxide concentration corrected for ambient carbon monoxide concentration in 108 jaundiced newborns (total serum bilirubin level >75th percentile) and 164 control newborns in our well-infant nursery, for the first 4 days after birth.RESULTS. Mean end-tidal carbon monoxide levels decreased in the control infants in the first 4 days but increased in the hyperbilirubinemic group. The differences between the jaundiced and nonjaundiced infants were statistically significant on all days.CONCLUSIONS. Before hospital discharge, most infants with bilirubin levels >75th percentile are producing significantly more bilirubin than those with lower bilirubin levels. Because the ability of newborns to conjugate bilirubin is significantly impaired in the first few days, even a small increase in the rate of production can contribute to the development of hyperbilirubinemia. These data suggest that increased heme catabolism is an important mechanism responsible for hyperbilirubinemia in the first 4 days after birth.

Bilirubin, the final product of heme catabolism, plays a crucial role in the cellular defense against oxidative and nitrosative stress. This study investigated the interaction of albumin-bound bilirubin, the circulating form of the bile pigment, with nitric oxide (NO), a gaseous modulator involved in many physiological functions but able to induce cytotoxicity and cell death if produced in excess. A short-lived endogenous S-nitrosothiol such as S-nitroso-cysteine was used as NO donor. In PBS without chelators, bilirubin was bound to human serum albumin with an apparent affinity of 1.6 +/- 0.2 microM (n = 4). Furthermore, albumin (2-20 microM) dose-dependently increased the half-life of BR (10 microM) exposed to S-nitroso-cysteine (100 microM) of 2.4 +/- 0.4 times (n = 4). Albumin-bound bilirubin was almost completely oxidized by S-nitroso-cysteine-derived NO, and biliverdin was the major product formed; this reaction seemed to be rather specific for albumin-bound bilirubin because when free bilirubin was reacted with S-nitroso-cysteine the formation of biliverdin was significantly lower. Uric acid and reduced glutathione, two well-known plasma antioxidants, at physiological concentrations protected albumin-bound bilirubin from NO-mediated oxidation. Taken together, these data suggest that albumin-bound bilirubin maintains its ability to interact with NO also in the bloodstream counteracting extracellular nitrosative reactions.

Bilirubin, a major product of heme catabolism, belongs to compounds with pleiotropic biologic effects. Although for decades it was considered as a metabolite dangerous for human health, recent data indicate that bilirubin exhibits potent antioxidant properties with substantial positive clinical consequences. In a recent issue of Pediatrics , Sedlak and Snyder1 comprehensively reviewed available data on the beneficial role of bilirubin. Although the article covers current knowledge of all the aspects of this topic almost completely, I would like to mention more data that further support a salutary role of bilirubin in the human body. In addition to studies cited in the Sedlak and Snyder article, total serum antioxidant capacity was found to correlate with serum bilirubin levels in our study on adult Gilbert syndrome (GS) patients, and this relation was confirmed in an in vitro study.2 In regard to the cited bilirubin oxidation metabolite study in septic patients, recent studies (mainly from Japan) demonstrated close correlation between these markers (called biopyrrins) and many other pathologic conditions including ischemic heart disease,3,4 congestive heart failure,5 atopic dermatitis,6 and surgical7,8 or even psychological stress.9 The same relationship was also found … Address correspondence to Libor Vitek, MD, PhD, 4th Department of Internal Medicine and Institute of Clinical Biochemistry and Laboratory Diagnostics, 1st Medical Faculty, Charles University of Prague, U Nemocnice 2, Praha 2, 128 08, Czech Republic. E-mail: vitek{at}cesnet.cz

The present review investigates the role of the cytoprotective enzyme heme oxygenase-1 (HO-1) in human diseases and explores strategies for its clinical use. In recent years, there has been a growing evidence, for the beneficial effects of some phytoconstituents via induction of HO-1 expression, contained in commonly used spices, fruits, and herbs, in preventing various pathologic conditions, including cancer, diabetes, and cardiovascular diseases. HO-1 catalyzes the rate-limiting step in heme catabolism to generate ferrous iron, carbon monoxide, and biliverdin. HO-1 is reported to play crucial roles in cellular protection, such as anti-inflammatory, anti-proliferative and anti-apoptotic effects. These evidences indicate that HO-1 may functions as a potential therapeutic target in various human diseases. The article highlights the current status of the development of the HO-1 modulation pathway using dietary phytoconstituents.

To the Editor .— I wish to add a few corrections and comments to the recent timely review by Sedlak and Snyder on bilirubin,1 the born-again benignant pigment. 1. It is not true that bilirubin formation is restricted to mammals. This is an obsolete, but frequently repeated, hypothesis that flies in the face of scientific evidence. Bilirubin and its conjugates occur in many nonmammals, although they may not be the principle bile pigments excreted in bile.2 For example, conjugates of bilirubin are excreted in bile in many fish species, and jaundice in fish is not unknown.3 Bilirubin conjugates are also present in bile of embryonic and adult chickens,4 and the observation in 1886 by Minkowski and Naunyn5 that arsine poisoning produced marked jaundice in normal but not hepatectomized geese was a key observation in the elucidation of the physiologic pathway of heme catabolism and the role of the reticuloendothelial system. Similarly, observations on the biosynthesis of bilirubin in ducks were important in elucidating bilirubin-formation pathways in humans.6 Bilirubin pigments also occur in alligators, snakes, and turtles,2 and a biliverdin reductase with substantial sequence homology to the human enzyme is present even in the lowly unicellular cyanobacterium Synechocystis .7 Therefore, the hoary idea that bilirubin occurs uniquely in …