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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

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.

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.

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.

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.

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...

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.

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.

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.

Bilirubin, the end product of heme catabolism, is generally regarded as a potentially cytotoxic, lipid-soluble waste product that needs to be excreted. However, bilirubin has been demonstrated to possess antioxidant properties as a chain breaking antioxidant and a scavenger of peroxyl radicals. Theses properties may be best evidents in neonates who may have undeveloped antioxidant enzymatic defenses. The aim of this study, therefore, was to evaluate the correlation between serum bilirubin and total antioxidant status in healthy term newborns.

Taurolithocholate has been implicated in human cholestatic syndromes. Its action is believed to be due to an alteration in liver plasma membrane composition. To investigate whether other membranes are similarly affected, we studied the effect of taurolithocholate on hepatic heme turnover by means of a new 14CO breath test. Between 2 and 7 h after taurolithocholate administration, 14CO production was significantly increased, suggesting increased heme catabolism. This was substantiated by the finding of a 47% reduction of microsomal cytochrome P450 content 3 h after taurolithocholate administration. There was a reciprocal increase of 50% in heme oxygenase activity, the key enzyme in heme catabolism. To probe the biological significance of these findings, we measured plasma disappearance of propranolol and antipyrine. Clearance of neither propranolol nor antipyrine was altered by acute taurolithocholate administration. Prolonged administration of taurolithocholate, by contrast, decreased metabolic clearance rate of antipyrine by 48%. This was accompanied by a 25% decrease in microsomal cytochrome P450 content. Our findings suggest that taurolithocholate affects composition and function of the smooth endoplasmic reticulum, and that its action is not limited to the liver plasma membrane.

Heme catabolism was monitored through the determination of total serum bilirubin and endogenous production of carbon monoxide in 6 healthy males before and after administration of 100 g of glucose orally and intravenously, respectively. To facilitate comparison, hyperbilirubinemia was induced through a 36-hr period of subtotal caloric restriction before the study. A decrease in production of carbon monoxide was seen after glucose given orally as well as intravenously, whereas total serum bilirubin decreased significantly only after glucose orally. It is suggested that oral as well as intravenous glucose administration temporarily inhibits heme catabolism, at least when given after a period of caloric restriction. In addition, oral glucose might have—probably via a gut-related factor—a facilitating effect on liver uptake of bilirubin.