Search tips
Search criteria 


Logo of nihpaAbout Author manuscriptsSubmit a manuscriptHHS Public Access; Author Manuscript; Accepted for publication in peer reviewed journal;
Semin Fetal Neonatal Med. Author manuscript; available in PMC 2011 June 1.
Published in final edited form as:
PMCID: PMC2859976

Metalloporphyrins in the management of neonatal hyperbilirubinemia


Neonatal jaundice in the first week of life is a common problem in newborns. It is due to an imbalance of bilirubin production and its elimination, which can lead to significantly elevated levels of circulating bilirubin or hyperbilirubinemia. Use of phototherapy and/or exchange transfusion are the current modes for treating neonatal hyperbilirubinemia and preventing any neurologic damage. These strategies, however, only remove bilirubin that has already been formed. Preventing the production of excess bilirubin may be a more logical approach. Synthetic heme analogs, metalloporphyrins, are competitive inhibitors of heme oxygenase (HO), the rate-limiting enzyme in bilirubin production, and their use has been proposed as an attractive alternative strategy for preventing or treating severe hyperbilirubinemia.

Keywords: Bilirubin, Heme oxygenase, Hyperbilirubinemia metalloporphyrin, Neonatal jaundice

[A] Introduction

The proposed use of metalloporphyrins (Mps) in the management of neonatal hyperbilirubinemia represents a targeted therapeutic intervention for the prevention of a transitional condition, which is sometimes exacerbated by exogenous factors.13 Therefore, a thorough understanding of the causes of neonatal jaundice is required and serves as a foundation for the rationale to reduce or inhibit the production of bilirubin as a way of controlling neonatal hyperbilirubinemia after birth.1,2,4,5 It is important to understand that neonatal jaundice is a syndrome with a variety of contributing causes. Historically, it has been the ‘jaundice syndrome’ that has been addressed categorically by non-specific maneuvers to eliminate excessive bilirubin from the body, after it has been produced, irrespective of the complex causation of its accumulation in an individual infant.13 The most popular first-line approach to treatment continues to be phototherapy, using light (actually blue light, a discrete part of the spectrum – from the mid-400 to low-500 nm range) to photoconvert the bilirubin molecule and form photoisomers that are excreted in bile without the need for hepatic conjugation to water-soluble glucuronides,6,7 the latter process being poorly developed in most infants in the first week after birth13 and genetically limited in some beyond that timeframe.8 Exchange transfusion is an even more invasive and risky treatment for severe hyperbilirubinemia13 or for hyperbilirubinemia unresponsive to phototherapy and is the last resort to prevent acute bilirubin-induced neurologic dysfunction (BIND) or rescue a patient in the context of BIND.9 An important point to be made is that there are limitations of such non-specific therapeutic interventions – they do not reflect personalized medicine, nor are they preventive. In fact, traditional classifications of pathologic conditions based on ‘appearance’, such as the condition of being jaundiced, are often not informing with respect to directing specific therapies to eliminate or mitigate any contributing causes of the pathologic condition. Moreover, any potential for prevention is lost because the therapies are non-specific and designed only to decrease jaundice after its appearance. In fact, much of medicine is reactive in this way and conditions are defined by deviations from the norm, with treatments mostly retrenching from pathology back towards normalcy.

[A] Neonatal hyperbilirubinemia

The first step then is to understand the phenotype of neonatal jaundice. It can be best defined as the result of an imbalance between bilirubin production and its elimination such that, when the rate at which bilirubin is produced exceeds the rate at which bilirubin is eliminated, the bilirubin load in the body increases.1,3,10 A certain amount of bilirubin can be retained in circulation, mainly bound to albumin. Even when this binding is sufficient, some bilirubin still can move outside the circulation and into tissues like the skin, with the infant becoming ‘visibly’ jaundiced. Visible jaundice is a sign that the bilirubin load is increasing, but it is a poor predictor of the concentration of bilirubin in circulation or other body compartments like the brain.11,12 Because bilirubin elimination is compromised in all babies in the first weeks after birth, bilirubin production becomes the major contributing cause to many kinds of pathologic jaundice in the newborn. Even the normal term newborn has increased bilirubin production (about two to threefold higher) compared to the adult, mainly due to an increased red cell mass and a shorter red cell lifespan.13 There are many other factors that can further enhance the production of the pigment, but hemolysis arising from a variety of causes is one of the most common and potentially most dangerous.13 The danger of hemolysis is its association with a greater risk for neurologic injury in the presence of severe hyperbilirubinemia. It is likely that an increased production of bilirubin in general confers a similar increased risk in any jaundice situation in which it is encountered, because it increases the load of bilirubin in the body and the amount of bilirubin that is likely to be in tissue for a given binding capacity. The rationale then for controlling production of the pigment in order to mitigate hyperbilirubinemia and avoid the increased risk for injury associated with hyperbilirubinemia in the context of increased bilirubin production becomes clearer and more persuasive.

[A] Inhibition of bilirubin production

The logical target for modulating bilirubin production is heme oxygenase (HO), the first and rate-limiting step in the production of bilirubin. Like most biologic targets, it is not singular in nature, but really a target in a context, which is complex. Moreover, there is more than one kind of HO,14,15 the inducible HO-1 and the constitutive HO-2, and possibly a third, about which less is known.16 In fact, the heme catabolic pathway can be described as a signaling network with many different connected pathways. The heme catabolic pathway itself represents a complex series of chemical reactions including the first and rate-limiting step which is catalyzed by HO and in the presence of NADPH (derived from the cytochrome P450 system) and molecular oxygen (O2) in a series of oxidations and reductions ultimately leading to the breaking of the IX-alpha methene bridge, creating biliverdin and releasing carbon monoxide (CO) and iron (Fe++) in equimolar proportions.17 The second step in the process also requires NADPH and is catalyzed by biliverdin reductase yielding bilirubin, also in equimolar relationship to CO and Fe++.

Because the pathway catabolizes heme, a pro-oxidant, and produces a potent antioxidant, bilirubin, it can be characterized as an antioxidant system, with the biliverdin–bilirubin interconversion ‘shuttle’ contributing to the redox state of the cell.18,19 Although iron, CO and bilirubin are all toxic at high levels, they are also all important molecules in connecting systems. The biliverdin–bilirubin shuttle may have antioxidant,20 anti-inflammatory,18 and anti-apoptotic effects.18 CO can cause vessel relaxation mediated directly through calcium-dependent potassium channels or through activation of soluble guanylyl cyclase (sGC), similar to nitric oxide (NO), increasing cyclic GMP and signaling vessel21,22 and smooth muscle relaxation23 as well as other effects on platelet aggregation,24 apoptosis,25 cell proliferation,26,27 and neurotransmission.26,27 CO may also inhibit proinflammatory cytokines through p38 MAPK28 and cause angiogenesis through increases in vascular endothelial growth factor (VEGF).29 Iron, through its participation in the ferritin-iron ATPase pump, may have antioxidant, anti-inflammatory, and anti-apoptotic effects.30 There are also many regulatory interactions between the HO and CO system and the nitric oxide synthase (NOS) and NO system.22,31 Some are positive and others are negative, and they are often countering. Thus, HO inhibitors not only affect heme catabolism and the production of bilirubin, a potential toxin in the newborn under some conditions; but they can also affect many other systems indirectly.31,32

Because CO and bilirubin are produced in equimolar amounts during the catabolism of heme, CO production, as estimated by carboxyhemoglobin (COHb) in circulation, end-tidal CO concentration corrected for ambient CO (ETCOc) and pulmonary excretion rates of CO (VeCO) can be used to estimate total body bilirubin formation,33 and thus can be used clinically to identify high risk situations in which bilirubin production is increased and the bilirubin load is likely to be high. The identification of high producers of bilirubin represents the direct targeting of individual infants who would benefit from modulation of bilirubin production as a contributing cause to their pathologic jaundice. Such biologic targeting avoids the inhibition of HO to below physiologic activity levels in babies who do not have abnormally elevated heme catabolism, reflecting not only normal transitional changes in heme catabolism, some of which are inducible, but also constitutive heme catabolism mediated by HO-2, and further avoids any unnecessary downstream direct or indirect effects on other important signaling systems.

Although CO production can serve as a good index of bilirubin production, it is important to recognize that there are other endogenous sources of CO, some of which may be important under some conditions, for example, photo-oxidation and lipid peroxidation.34 However, under most circumstances encountered in the newborn who does not have pulmonary disease with exposure to high inspired O2, heme degradation accounts for greater than 80% of the CO produced and excreted, with 70% of that derived from senescing red blood cells, 10% from ineffective erythropoiesis, and 20% from the degradation of other hemoproteins.1,3 Under some of the pathologic conditions encountered in the newborn, such as hematoma formation, polycythemia, and hemolytic disease, the proportion of CO coming from heme degradation may be even greater. Thus, CO in breath is probably the most sensitive index of clinically important hemolysis and the best way to target babies with increased production of bilirubin.33 Although clinical and epidemiologic risk factors can be used to target potential candidates for drug therapy, such targeting is unavoidably less precise. For example, only half of the babies with ABO heterospecificity and a positive direct Coombs’ test have hemolysis.35 Conversely, some babies with ABO heterospecificity and a negative direct Coombs’ test have increased hemolytic rates.35 These circumstances are readily identifiable by estimating CO production.36

Early work by Maines, Drummond and Kappas,4,37,38 began a systematic study of Mps, synthetic structural analogues or metalloporphyrins (Mps) of heme, as a new class of drugs for the modulation of bilirubin production. Over several decades, they were joined by a host of other investigators.5,3944 Many different Mps have been investigated with respect to their efficacy and safety. Only tin protoporphyrin (SnPP)45 and later tin mesoporphyrin (SnMP)4648 have been studied in human neonates. SnPP was abandoned early because of its photosensitizing properties,49,50 despite being highly efficacious. Although SnMP is also photosensitizing,51 its greater potency has allowed for its use at lower doses with minimal apparent photoreactivity in the clinical setting, especially if light exposure is avoided or restricted to a narrow part of the spectrum.7 In mouse studies, we have found that at high oral doses [30 μmol/kg/body weight (BW)], SnMP significantly inhibits brain HO activity as well as inhibits liver HO activity. Furthermore, significant induction of HO-1 expression was found in the liver and brain. When lower doses were tested, significant inhibition of brain HO activity was still observed at a dose of 7.5 μmol/kg BW, but induction of HO-1 in brain and liver were minimal.52 At still lower doses (3.75 μmol/kg BW), long-term potent inhibition of HO is still observed with negligible effects on HO-1 transcription,53 as well as avoiding potential direct effects on other enzyme systems, such as sGC and NOS.32 The use of SnMP for the prevention of severe neonatal hyperbilirubinemia has also been reviewed in considerable detail.54

Nonetheless, the ideal antihyperbilirubinemic drug would contain a biocompatible central metal, cause potent HO inhibition, have negligible degradation, inhibition of other enzymes, photoreactivity, HO-1 upregulation, and have an optimal duration of action (which would be no more than days) (Table I).54,55 Alternative Mps to SnMP do exist and are being studied because they have many of these desirable features, including being photo-inert, which have been reviewed in detail previously.55 Some, such as chromium mesoporphyrin (CrMP)56,57 and zinc bis glycol (ZnBG),58,59 are orally absorbable; and zinc protoporphyrin (ZnPP) is naturally occurring and has no apparent photoreactivity in vivo. In fact, orally absorbed compounds may be more likely to exhibit effects in the liver and spleen with less distribution to other tissues particularly if they can be used at lower doses. Some of these compounds also appear not to upregulate substantially the HO-1 gene (e.g. ZnPP and ZnBG), while maintaining their inhibitory potency.60,61

Table 1
Most desirable properties of an anti-hyperbilirubinemia drug

CrMP at a dose of 15 μmol/kg BW is orally absorbed by the newborn mouse, inhibits liver HO activity in an age-dependent manner 24 h after administration without affecting spleen and brain HO activity.62 When the in vivo effects of prophylactic oral CrMP on HO activity following a single oral heme load (30 μmol/kg BW) were investigated, CrMP abolished the heme-mediated increases in liver and spleen significantly.56 After a second heme load, a low dose of CrMP (3.75 μmol/kg BW) was effective in inhibiting heme-induced increases in liver HO activity in the spleen, but not in the brain.56

ZnBG is also effective towards inhibiting liver HO activity at a lower dose (3.75 μmol/kg BW) and more quickly (with 3 h of administration) than CrMP, and does not affect spleen or brain HO activity.59 Neither compound appears to induce any changes in HO-1 protein or gene transcription levels. These properties also make CrMP and ZnBG attractive alternative compounds to SnMP since they have great efficacy of short duration with minimal or no long-term effects on HO-1 gene regulation.

There is now additional motivation for using an Mp HO-1 inhibitor or some other drugs to inhibit HO-1 or lower bilirubin levels transiently after birth, because of recent findings in a randomized controlled trial of aggressive versus conservative phototherapy for infants with extremely low birth weight.63 Although the primary outcome of the study revealed no clear difference between both groups with respect to death or neurodevelopmental impairment, a subgroup analysis suggested that infants weighing between 501 and 750 g in the aggressive phototherapy group, the smallest and most translucent babies, might have an increased risk of death. This was further supported by Bayesian analyses. More study is required to demonstrate that aggressive phototherapy does not increase the mortality of infants ≤750 g, but there is biologic plausibility for this possibility. In order to resolve this question, a randomized controlled trial to compare aggressive phototherapy with Mp therapy in order to avoid severe hyperbilirubinemia is needed.

Still, a pharmacologic approach to managing newborn jaundice in the smallest babies could be an attractive alternative. Other compounds structurally different from Mps have been found to possess HO-inhibiting properties. For example, peptide inhibitors, originally developed for use in transplantation survival studies, have been found to inhibit HO activity in vitro in a dose-dependent manner.64 However, administration of peptides in mice resulted in an upregulation of HO-1 mRNA and protein, as well as HO activity in liver, spleen, and kidney. Consequently, human studies using these peptides for the treatment of hyperbilirubinemia have not been performed. In addition, imidazole dioxolanes, compounds designed to inhibit cholesterol production, have also been found to inhibit in vitro and in vivo HO activity.6568 These compounds have a high selectivity for inhibiting the inducible HO-1.66,68 Some of these compounds have been found to affect other important enzymes, such as NOS and sGC, in rat tissues.65 In in-vivo studies using one of these compounds, Azalanstat, we demonstrated that HO activity in the spleen, brain, and liver could be inhibited. However, 24 h after treatment, spleen HO activity, HO-1 protein, and HO-1 mRNA levels are significantly increased.67

[A] Conclusion

The use of Mps in the management of neonatal hyperbilirubinemia represents an opportunity to introduce targeted therapeutic intervention for prevention of neonatal jaundice into clinical practice. Furthermore, an anticipatory approach to neonatal jaundice is the ideal tactic, perhaps even with antenatal diagnosis of genetic vulnerabilities, such as polymorphisms known to be associated with jaundice, for example, having fewer than normal GT repeats in the HO-1 promoter, or mutations in UGT1A1 or OATPIB1 contributing to impaired conjugation or hepatic uptake and slower elimination of the pigment.8,11,69,70 The interaction of genes could also be anticipated – for example, glucose-6-phosphate dehydrogenase (G6PD) deficiency and Gilbert’s syndrome, as has been reported by Kaplan et al.71,72 With such anticipation, infants could then be monitored non-invasively after birth for increased production of bilirubin, with early prophylactic treatment of high producers and poor eliminators with antihyperbilirubinemic drugs. Such genetic and phenotypic targeting would finally bring rationality to the management of neonatal jaundice and largely avoid the risk of toxicity from bilirubin.

Practice points

  • To understand the causation of neonatal hyperbilirubinemia.
  • To understand the use of metalloporphyrins (Mps) or other potential alternative compounds to prevent or treat severe neonatal hyperbilirubinemia.
  • To understand the potential side-effects and safety concerns of Mps.
  • To understand the current state of Mp research.

Research directions

  • Comparison of the efficacy of aggressive phototherapy with Mp therapy to prevent the development of severe hyperbilirubinemia.
  • Evaluation of the potential phototoxic effects, if any, of chromium mesoporphyrin and zinc bis glycol porphyrin.


Funding sources: None.


Conflict of interest statement

None declared.

Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

[A] References

1. Stevenson DK, Wong RJ, Hintz SR, Vreman HJ. The jaundiced newborn. Understanding and managing transitional hyperbilirubinemia. Minerva Pediatr. 2002;54:373–82. [PubMed]
2. Dennery PA, Seidman DS, Stevenson DK. Neonatal hyperbilirubinemia. N Engl J Med. 2001;344:581–90. [PubMed]
3. Stevenson DK, Wong RJ, DeSandre GH, Vreman HJ. A primer on neonatal jaundice. Adv Pediatr. 2004;51:263–88. [PubMed]
4. Kappas A, Drummond GS, Simionatto CS, Anderson KE. Control of heme oxygenase and plasma levels of bilirubin by a synthetic heme analogue, tin-protoporphyrin. Hepatology. 1984;4:336–41. [PubMed]
5. Stevenson DK, Rodgers PA, Vreman HJ. The use of metalloporphyrins for the chemoprevention of neonatal jaundice. Am J Dis Child. 1989;143:353–6. [PubMed]
6. McDonagh AF, Lightner DA. Phototherapy and the photobiology of bilirubin. Semin Liver Dis. 1988;8:272–83. [PubMed]
7. Vreman HJ, Wong RJ, Stevenson DK. Phototherapy: current methods and future directions. Semin Perinatol. 2004;28:326–33. [PubMed]
8. Watchko JF, Daood MJ, Biniwale M. Understanding neonatal hyperbilirubinaemia in the era of genomics. Semin Neonatol. 2002;7:143–52. [PubMed]
9. American Academy of Pediatrics. Management of hyperbilirubinemia in the newborn infant 35 or more weeks of gestation. Pediatrics. 2004;114:297–316. [PubMed]
10. Kaplan M, Muraca M, Hammerman C, et al. Imbalance between production and conjugation of bilirubin: a fundamental concept in the mechanism of neonatal jaundice. Pediatrics. 2002;110:e47. [PubMed]
11. Watchko JF. Kernicterus and the molecular mechanisms of bilirubin-induced CNS injury in newborns. Neuromolecular Med. 2006;8:513–30. [PubMed]
12. Watchko JF, Daood MJ, Mahmood B, Vats K, Hart C, Ahdab-Barmada M. P-glycoprotein and bilirubin disposition. J Perinatol. 2001;21(Suppl 1):S43–7. [PubMed]
13. Landaw SA, Winchell HS, Boone RF. Measurement of endogenous carbon monoxide production in hemolytic disease of the inborn. Clin Res. 1971;19:208A.
14. Maines MD. Heme oxygenase: function, multiplicity, regulatory mechanisms, and clinical applications. FASEB J. 1988;2:2557–68. [PubMed]
15. Maines MD. Heme oxygenase: clinical applications and functions. Boca Raton: CRC Press; 1992.
16. McCoubrey WK, Jr, Huang TJ, Maines MD. Isolation and characterization of a cDNA from the rat brain that encodes hemoprotein heme oxygenase-3. Eur J Biochem. 1997;247:725–32. [PubMed]
17. Tenhunen R, Marver HS, Schmid R. The enzymatic conversion of heme to bilirubin by microsomal heme oxygenase. Proc Natl Acad Sci USA. 1968;61:748–55. [PubMed]
18. Baranano DE, Rao M, Ferris CD, Snyder SH. Biliverdin reductase: a major physiologic cytoprotectant. Proc Natl Acad Sci USA. 2002;99:16093–8. [PubMed]
19. Foresti R, Green CJ, Motterlini R. Generation of bile pigments by haem oxygenase: a refined cellular strategy in response to stressful insults. Biochem Soc Symp. 2004:177–92. [PubMed]
20. Stocker R, Yamamoto Y, McDonagh AF, Glazer AN, Ames BN. Bilirubin is an antioxidant of possible physiological importance. Science. 1987;235:1043–6. [PubMed]
21. Furchgott RF, Jothianandan D. Endothelium-dependent and -independent vasodilation involving cyclic GMP: relaxation induced by nitric oxide, carbon monoxide and light. Blood Vessels. 1991;28:52–61. [PubMed]
22. Marks GS, Brien JF, Nakatsu K, McLaughlin BE. Does carbon monoxide have a physiological function? Trends Pharmacol Sci. 1991;12:185–8. [PubMed]
23. Acevedo CH, Ahmed A. Hemeoxygenase-1 inhibits human myometrial contractility via carbon monoxide and is upregulated by progesterone during pregnancy. J Clin Invest. 1998;101:949–55. [PMC free article] [PubMed]
24. Brune B, Ullrich V. Inhibition of platelet aggregation by carbon monoxide is mediated by activation of guanylate cyclase. Mol Pharmacol. 1987;32:497–504. [PubMed]
25. Brouard S, Otterbein LE, Anrather J, et al. Carbon monoxide generated by heme oxygenase 1 suppresses endothelial cell apoptosis. J Exp Med. 2000;192:1015–26. [PMC free article] [PubMed]
26. Prabhakar NR, Dinerman JL, Agani FH, Snyder SH. Carbon monoxide: a role in carotid body chemoreception. Proc Natl Acad Sci USA. 1995;92:1994–7. [PubMed]
27. Leinders-Zufall T, Shepherd GM, Zufall F. Regulation of cyclic nucleotide-gated channels and membrane excitability in olfactory receptor cells by carbon monoxide. J Neurophysiol. 1995;74:1498–508. [PubMed]
28. Ryter SW, Otterbein LE, Morse D, Choi AM. Heme oxygenase/carbon monoxide signaling pathways: regulation and functional significance. Mol Cell Biochem. 2002;234–235:249–63. [PubMed]
29. Cudmore M, Ahmad S, Al-Ani B, et al. Negative regulation of soluble Flt-1 and soluble endoglin release by heme oxygenase-1. Circulation. 2007;115:1789–97. [PubMed]
30. Loboda A, Jazwa A, Grochot-Przeczek A, et al. Heme oxygenase-1 and the vascular bed: from molecular mechanisms to therapeutic opportunities. Antioxid Redox Signal. 2008;10:1767–812. [PubMed]
31. Odrcich MJ, Graham CH, Kimura KA, et al. Heme oxygenase and nitric oxide synthase in the placenta of the guinea pig during gestation. Placenta. 1998;19:509–16. [PubMed]
32. Appleton SD, Chretien ML, McLaughlin BE, et al. Selective inhibition of heme oxygenase, without inhibition of nitric oxide synthase or soluble guanylyl cyclase, by metalloporphyrins at low concentrations. Drug Metab Dispos. 1999;27:1214–9. [PubMed]
33. Stevenson DK, Vreman HJ. Carbon monoxide and bilirubin production in neonates. Pediatrics. 1997;100:252–4. [PubMed]
34. Vreman HJ, Wong RJ, Sanesi CA, Dennery PA, Stevenson DK. Simultaneous production of carbon monoxide and thiobarbituric acid reactive substances in rat tissue preparations by an iron–ascorbate system. Can J Physiol Pharmacol. 1998;76:1057–65. [PubMed]
35. Kaplan M, Na’amad M, Kenan A, et al. Failure to predict hemolysis and hyperbilirubinemia by IgG subclass in blood group A or B infants born to group O mothers. Pediatrics. 2009;123:e132–7. [PubMed]
36. Ostrander CR, Cohen RS, Hopper AO, Cowan BE, Stevens GB, Stevenson DK. Paired determinations of blood carboxyhemoglobin concentration and carbon monoxide excretion rate in term and preterm infants. J Lab Clin Med. 1982;100:745–55. [PubMed]
37. Drummond GS, Kappas A. Prevention of neonatal hyperbilirubinemia by tin protoporphyrin IX, a potent competitive inhibitor of heme oxidation. Proc Natl Acad Sci USA. 1981;78:6466–70. [PubMed]
38. Maines MD. Zinc-protoporphyrin is a selective inhibitor of heme oxygenase activity in the neonatal rat. Biochim Biophys Acta. 1981;673:339–50. [PubMed]
39. Cornelius CE, Rodgers PA. Prevention of neonatal hyperbilirubinemia in rhesus monkeys by tin-protoporphyrin. Pediatr Res. 1984;18:728–30. [PubMed]
40. Stout DL, Becker FF. The effects of tin-protoporphyrin administration on hepatic xenobiotic metabolizing enzymes in the juvenile rat. Drug Metab Dispos. 1988;16:23–6. [PubMed]
41. Davis DR, Bail SP. Tin-protoporphyrin suppression of hyperbilirubinemia in the jaundiced Gunn rat. Dev Pharmacol Ther. 1988;11:281–7. [PubMed]
42. Land EJ, McDonagh AF, McGarvey DJ, Truscott TG. Photophysical studies of tin(IV)-protoporphyrin: potential phototoxicity of a chemotherapeutic agent proposed for the prevention of neonatal jaundice. Proc Natl Acad Sci USA. 1988;85:5249–53. [PubMed]
43. Mitrione SM, Villalon P, Lutton JD, Levere RD, Abraham NG. Inhibition of human adult and fetal heme oxygenase by new synthetic heme analogues. Am J Med Sci. 1988;296:180–6. [PubMed]
44. Valaes TN, Harvey-Wilkes K. Pharmacologic approaches to the prevention and treatment of neonatal hyperbilirubinemia. Clin Perinatol. 1990;17:245–73. [PubMed]
45. Kappas A, Drummond GS, Manola T, Petmezaki S, Valaes T. Sn-protoporphyrin use in the management of hyperbilirubinemia in term newborns with direct Coombs-positive ABO incompatibility. Pediatrics. 1988;81:485–97. [PubMed]
46. Martinez JC, Garcia HO, Otheguy LE, Drummond GS, Kappas A. Control of severe hyperbilirubinemia in full-term newborns with the inhibitor of bilirubin production Sn-mesoporphyrin. Pediatrics. 1999;103:1–5. [PubMed]
47. Valaes T, Petmezaki S, Henschke C, Drummond GS, Kappas A. Control of jaundice in preterm newborns by an inhibitor of bilirubin production: studies with tin-mesoporphyrin. Pediatrics. 1994;93:1–11. [PubMed]
48. Reddy P, Najundaswamy S, Mehta R, Petrova A, Hegyi T. Tin-mesoporphyrin in the treatment of severe hyperbilirubinemia in a very-low-birth-weight infant. J Perinatol. 2003;23:507–8. [PubMed]
49. Keino H, Nagae H, Mimura S, Watanabe K, Kashiwamata S. Dangerous effects of tin-protoporphyrin plus photoirradiation on neonatal rats. Eur J Pediatr. 1990;149:278–9. [PubMed]
50. Hintz SR, Vreman HJ, Stevenson DK. Mortality of metalloporphyrin-treated neonatal rats after light exposure. Dev Pharmacol Ther. 1990;14:187–92. [PubMed]
51. Vreman HJ, Gillman MJ, Downum KR, Stevenson DK. In vitro generation of carbon monoxide from organic molecules and synthetic metalloporphyrins mediated by light. Dev Pharmacol Ther. 1990;15:112–24. [PubMed]
52. Wong RJ, Morioka I, Vreman HJ, Stevenson DK. Oral absorptivity of tin mesoporphyrin (SnMP) and distribution into the brain of young mice. Pediatr Res. 2005;57:A1277.
53. Morioka I, Wong RJ, Muchova L, Vreman HJ, Stevenson DK. Effect of tin mesoporphyrin on heme oxygenase activity following repeated heme loads in newborn mice. EPAS2006. 2006;59:5575.485.
54. Wong RJ, Bhutani VK, Vreman HJ, Stevenson DK. Tin mesoporphyrin for the prevention of severe neonatal hyperbilirubinemia. NeoReviews. 2007;8:e77–84.
55. Vreman HJ, Wong RJ, Stevenson DK. Alternative metalloporphyrins for the treatment of neonatal jaundice. J Perinatol. 2001;21(Suppl 1):S108–13. [PubMed]
56. Morisawa T, Wong RJ, Xiao H, Bhutani VK, Vreman HJ, Stevenson DK. Inhibition of heme oxygenase activity by chromium mesoporphyrin in the heme-loaded newborn mouse. E-PAS2008. 2008:6130.9.
57. He CX, Morisawa T, Zhao H, Wong RJ, Stevenson DK. Age-dependent expression of heme oxygenase-1 in mice following oral administration of chromium mesoporphyrin. J Invest Med. 2009;57:177. (#286)
58. Vreman HJ, Lee OK, Stevenson DK. In vitro and in vivo characteristics of a heme oxygenase inhibitor: ZnBG. Am J Med Sci. 1991;302:335–41. [PubMed]
59. Campbell CM, Morisawa T, Zhao H, Wong RJ, Stevenson DK. Dose-dependent effects of zinc bis glycol porphyrin on the expression of heme oxygenase in newborn mice. J Invest Med. 2009;57:177. (#287)
60. Hajdena-Dawson M, Zhang W, Contag PR, et al. Effects of metalloporphyrins on heme oxygenase-1 transcription: correlative cell culture assays guide in vivo imaging. Molec Imag. 2003;2:138–49. [PubMed]
61. Zhang W, Contag PR, Hardy J, et al. Selection of potential therapeutics based on in vivo spatiotemporal transcription patterns of heme oxygenase-1. J Mol Med. 2002;80:655–64. [PubMed]
62. Xiao H, Morisawa T, Wong RJ, Stevenson DK. Short- and long-term effects of heme oxygenase activity by chromium mesoporphyrin in newborn mice. E-PAS. 2008:6130.8.
63. Morris BH, Oh W, Tyson JE, et al. Aggressive vs. conservative phototherapy for infants with extremely low birth weight. N Engl J Med. 2008;359:1885–96. [PMC free article] [PubMed]
64. Iyer S, Woo J, Cornejo MC, et al. Characterization and biological significance of immunosuppressive peptide D2702.75-84(E → V) binding protein. Isolation of heme oxygenase-1. J Biol Chem. 1998;273:2692–7. [PubMed]
65. Vlahakis JZ, Kinobe RT, Bowers RJ, Brien JF, Nakatsu K, Szarek WA. Synthesis and evaluation of azalanstat analogues as heme oxygenase inhibitors. Bioorg Medi Chem Lett. 2005;15:1457–61. [PubMed]
66. Vlahakis JZ, Kinobe RT, Bowers RJ, Brien JF, Nakatsu K, Szarek WA. Imidazole-dioxolane compounds as isozyme-selective heme oxygenase inhibitors. J Med Chemy. 2006;49:4437–41. [PubMed]
67. Morisawa T, Wong RJ, Bhutani VK, Vreman HJ, Stevenson DK. Inhibition of heme oxygenase activity in newborn mice by azalanstat. Can J Physiol Pharmacol. 2008;86:651–9. [PubMed]
68. Kinobe RT, Vlahakis JZ, Vreman HJ, et al. Selectivity of imidazole-dioxolane compounds for in vitro inhibition of microsomal haem oxygenase isoforms. Br J Pharmacol. 2006;147:307–15. [PMC free article] [PubMed]
69. Lin Z, Fontaine J, Watchko JF. Coexpression of gene polymorphisms involved in bilirubin production and metabolism. Pediatrics. 2008;122:e156–62. [PubMed]
70. Kaplan M, Hammerman C, Rubaltelli FF, et al. Hemolysis and bilirubin conjugation in association with UDP-glucuronosyltransferase 1A1 promoter polymorphism. Hepatology. 2002;35:905–11. [PubMed]
71. Kaplan M, Renbaum P, Levy-Lahad E, Hammerman C, Lahad A, Beutler E. Gilbert syndrome and glucose-6-phosphate dehydrogenase deficiency: a dose-dependent genetic interaction crucial to neonatal hyperbilirubinemia. Proc Natl Acad Sci USA. 1997;94:12128–32. [PubMed]
72. Kaplan M, Hammerman C. Glucose-6-phosphate dehydrogenase deficiency: a hidden risk for kernicterus. Semin Perinatol. 2004;28:356–64. [PubMed]