Repression by Hematin of Porphyrin Biosynthesis in Erythrocyte Precursors in Congenital Erythropoietic Porphyria

Watson, C. J.; Bossenmaier, Irene; Cardinal, Ruth; Petryka, Z.J.

doi:10.1073/pnas.71.2.278

Cited by 49 publications

(13 citation statements)

References 28 publications

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“…The excessive porphyrin concentrations in erythrocytes induce fragility with osmotic hemolysis [30]. Consequent spleen enlargement can be found in nearly all patients and liver enlargement in some [20].…”

Section: Hematological Findingsmentioning

confidence: 99%

Congenital Erythropoietic Porphyria

Fritsch

Lang

Bolsen

et al. 1998

Skin Pharmacol Physiol

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Congenital erythropoietic porphyria (CEP) is one of the rarest autosomal-recessive disorders of the porphyrin metabolism caused by the homozygous defect of uroporphyrinogen III cosynthase. High amounts of uroporphyrin I accumulate in all cells and tissues, reflected by an increased erythrocyte porphyrin concentration and excretion of high porphyrin amounts in urine and feces. Dermal deposits of uroporphyrin frequently induce a dramatic phototoxic oxygen-dependent skin damage with extensive ulcerations and mutilations. Splenomegaly and hemolytic anemia are typical internal symptoms. Skeletal changes such as osteolysis and calcifications are frequent. Up to date 130 cases of CEP have been published. Splenectomy and erythrocyte transfusions showed some beneficial effect. Bone marrow transplantation was performed in 3 patients and stem cell transplantation in 1. The best therapy is the avoidance of sunlight. We give a report on our latest cases of CEP.

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Section: Hematological Findingsmentioning

confidence: 99%

Congenital Erythropoietic Porphyria

Fritsch

Lang

Bolsen

et al. 1998

Skin Pharmacol Physiol

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“…Suppression of the rate of heme breakdown by heme oxygenase inhibition would presumably lead to the sequestration of heme in the circulation or in various tissues. The consequences of this in the newborn are not known; in the adult, however, heme (as hematin) has been administered intravenously (doses =100-400 mg per infusion 1 or 2 times daily) for treatment of the hereditary erythroid (30,31) and hepatic porphyrias (32)(33)(34) as well as lead poisoning (35), and with the exception ofa single individual (36) …”

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confidence: 99%

Prevention of neonatal hyperbilirubinemia by tin protoporphyrin IX, a potent competitive inhibitor of heme oxidation.

Drummond¹,

Kappas²

1981

Proc. Natl. Acad. Sci. U.S.A.

277

201

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The effects of various metalloporphyrins on hepatic heme oxygenase (EC 1. 14.99.3) activity were examined in order to identify compounds that could inhibit heme degradation to bile pigment and might therefore be utilized to suppress the development of hyperbilirubinemia in the newborn. Among nine metal-protoporhyrin IX chelates (i.e., metal-hemes) studied, Snheme, Mn-heme, and Zn-heme substantially diminished heme oxygenase activity in vivo in the rat. These metalloporphyrins act as competitive inhibitory.substrates in the heme oxygenase reaction but are not themselves oxidatively. degraded. Sn.cheme was the most potent enzyme inhibitor (1I = 0.911 FAM) in liver, spleen, kidney, and .skin. Sn-heme administered to newborn animals within the first 72 hr after birth blocked the postnatal increase in heme oxygenase activity that occurs in various tissues. Its effect on the enzyme levels was prompt and protracted. Sn-heme administration also entirely prevented the development of hyperbilirubinemia that normally occurs postnatally. The effect of the metalloporphyrin in lowering the increased concentrations of serum bilirubin in neonates was prompt (within 1 day) and persisted throughout the 42 days after birth. No deleterious effects of Snheme treatment of the newborn were observed. This demonstrates that a synthetic metalloporphyrin that is a potent competitive inhibitor of heme oxidation can, when administered to the newborn, also prevent the hyperbilirubinemia that normally develops postnatally. The potential clinical implications ofthese findings are evident, and it is suggested that the pharmacological properties of Sn-heme and related synthetic metalloporphyrins merit further study. Chemical blockade of the postnatal induction of heme oxygenase activity [heme,hydrogen-donor In this study we examined the ability of nine metalloporphyrins to alter heme oxygenase synthesis or function in liver, spleen, and other tissues of the rat. Of these compounds three markedly inhibited heme degradation by the enzyme; three substantially enhanced this process,. presumably by inducing heme oxygenase; and three had intermediate effects on the enzyme. Two of these. metal-protoporphyrin IX complexes (Snheme and Mn-heme) were employed in whole animal. studies to determine whether the ability to block heme oxygenase activity demonstrated in vitro could be shown to have physiological expression by also blocking the development of postnatal hyperbilirubinemia in the neonate during the 6-week period after birth.We report here that a metalloporphyrin, Sn-heme, which in vitro acts as a potent competitive substrate for heme in the heme oxygenase reaction can also, when administered to newborn animals, entirely prevent the hyperbilirubinemia that develops in the postnatal period.MATERIALS AND METHODS Materials. Male (160-200 g) and 15-day-pregnant female Sprague-Dawley rats purchased from Holtzman (Madison, WI) were used. To the extent possible pregnancy was synchronized in the latter group of animals so that large numbers of newb...

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“…Therapeutic interventions in the past have included protection from sunlight (which is essential until definitive treatment is implemented), beta-carotene to reduce oxidative damage, 1,2 splenectomy to decrease anemia and thrombocytopenia, 1-12 transfusion regimens 13 and i.v. hematin (oxidized free heme) therapy 8,[14][15][16] to suppress hemoglobin production, adsorbents to bind to porphyrins and increase their excretion, 17,[20][21][22] hydroxyurea, 13,23,24 and steroids. 13,[17][18][19][20] The most effective therapy would be one that increases uroporphyrinogen III cosynthase activity into the normal range, as it is reduced to 0 to 40% of normal in erythrocytes and fibroblasts of patients with CEP (approximately 50% of normal in carriers).…”

Section: Discussionmentioning

confidence: 99%

Treatment of congenital erythropoietic porphyria in children by allogeneic stem cell transplantation: a case report and review of the literature

Shaw

Mancini

McConnell

et al. 2001

Bone Marrow Transplant

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Summary:Congenital erythropoietic porphyria (CEP) is a rare autosomal recessive disorder of porphyrin metabolism in which the genetic defect is the deficiency of uroporphyrinogen III cosynthase (UIIIC). Deficiency of this enzyme results in an accumulation of high amounts of uroporphyrin I in all tissues leading to hemolytic anemia, splenomegaly, erythrodontia, bone fragility, exquisite photosensitivity and mutilating skin lesions. We describe the case of a 23-month-old boy who was cured of his CEP by a matched-sibling allogeneic bone marrow transplant, and review the published clinical experience regarding transplantation in this disease. He is alive and disease-free 15 months post transplant. All of his disease manifestations except for the erythrodontia have resolved. His UIIIC level and stool and erythrocyte porphyrin metabolites have almost completely corrected. He is the sixth child reported to be cured of this disease by stem cell transplantation, five cases being long-term survivors. If patients with this disease have an HLA-matched sibling, then stem cell transplantation should be strongly considered because this is currently the only known curative therapy. Bone Marrow Transplantation (2001) 27, 101-105. Keywords: congenital erythropoietic porphyria; porphyria; stem cell transplantation; bone marrow transplantation Congenital erythropietic porphyria (CEP), or Gunther's disease, is one of the rarest of the porphyrias, a group of metabolic disorders in which excessive quantities of porphyrins or their precursors are produced. This autosomal recessive disorder is caused by a defect of the enzyme uroporphyrinogen III cosynthase (UIIIC) that leads to an accumulation of uroporphyrinogen I and coproporphyrinogen I in all tissues. The primary clinical manifestations of this accumulation include erythrodontia, bone fragility, hypertrichosis,

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Repression by Hematin of Porphyrin Biosynthesis in Erythrocyte Precursors in Congenital Erythropoietic Porphyria

Cited by 49 publications

References 28 publications

Congenital Erythropoietic Porphyria

Congenital Erythropoietic Porphyria

Prevention of neonatal hyperbilirubinemia by tin protoporphyrin IX, a potent competitive inhibitor of heme oxidation.

Treatment of congenital erythropoietic porphyria in children by allogeneic stem cell transplantation: a case report and review of the literature

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