Distribution of protoporphyrin IX in erythrocytes in a case of acquired erythropoietic protoporphyria

Rat liver mitochondria accumulate protoporphyrin IX from the suspending medium into the inner membrane in parallel with the magnitude of the transmembrane K+ gradient (K+in/K+out). Only protoporphyrin IX taken up in parallel with the transmembrane K+ gradient is available for haem synthesis. Coproporphyrins (isomers I and III) are not taken up by the mitochondria. The results support the suggestion by Elder & Evans [(1978) Biochem. J. 172, 345-347] that the prophyrin to be taken up by the inner mitochondrial membrane belongs to the protoporphyrin(ogen) IX series. Protoporphyrin IX at concentrations above 15 nmol/mg of protein has detrimental effects on the structural and functional integrity of the mitochondria. The relevance of these effects to the hepatic lesion in erythropoietic protoporphyria is discussed.

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The essential role of the transporter ABCG2 in the pathophysiology of erythropoietic protoporphyria

Science Advances ◽

10.1126/sciadv.aaw6127 ◽

2019 ◽

Vol 5 (9) ◽

pp. eaaw6127 ◽

Cited By ~ 3

Author(s):

Pengcheng Wang ◽

Madhav Sachar ◽

Jie Lu ◽

Amina I. Shehu ◽

Junjie Zhu ◽

...

Keyword(s):

Essential Role ◽

Protoporphyrin Ix ◽

Heme Biosynthesis ◽

Biosynthesis Pathway ◽

Efflux Transporter ◽

Inherited Disease ◽

Loss Of Function ◽

Erythropoietic Protoporphyria

Erythropoietic protoporphyria (EPP) is an inherited disease caused by loss-of-function mutations of ferrochelatase, an enzyme in the heme biosynthesis pathway that converts protoporphyrin IX (PPIX) into heme. PPIX accumulation in patients with EPP leads to phototoxicity and hepatotoxicity, and there is no cure. Here, we demonstrated that the PPIX efflux transporter ABCG2 (also called BCRP) determines EPP-associated phototoxicity and hepatotoxicity. We found that ABCG2 deficiency decreases PPIX distribution to the skin and therefore prevents EPP-associated phototoxicity. We also found that ABCG2 deficiency protects against EPP-associated hepatotoxicity by modulating PPIX distribution, metabolism, and excretion. In summary, our work has uncovered an essential role of ABCG2 in the pathophysiology of EPP, which suggests the potential for novel strategies in the development of therapy for EPP.

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Breast cancer resistance protein (Bcrp1/Abcg2) is expressed in the harderian gland and mediates transport of conjugated protoporphyrin IX

AJP Cell Physiology ◽

10.1152/ajpcell.00359.2006 ◽

2007 ◽

Vol 292 (6) ◽

pp. C2204-C2212 ◽

Cited By ~ 23

Author(s):

Johan W. Jonker ◽

Sandra Musters ◽

Maria L. H. Vlaming ◽

Torsten Plösch ◽

Karin E. R. Gooijert ◽

...

Keyword(s):

Breast Cancer ◽

Breast Cancer Resistance Protein ◽

Protoporphyrin Ix ◽

Harderian Gland ◽

Cancer Resistance ◽

Erythropoietic Protoporphyria ◽

Physiological Conditions ◽

High Affinity ◽

Expression Site ◽

Resistance Protein

Proper regulation of intracellular levels of protoporphyrin IX (PPIX), the direct precursor of heme, is important for cell survival. A deficiency in ferrochelatase, which mediates the final step in heme biosynthesis, leads to erythropoietic protoporphyria (EPP), a photosensitivity syndrome caused by the accumulation of PPIX in the skin. We have previously shown that mice with a deficiency in the ABC transporter Bcrp1/Abcg2 display a novel type of protoporphyria. This protoporphyria is mild compared with ferrochelatase-dependent EPP, and in itself not sufficient to cause phototoxicity, but it might exacerbate the consequences of other porphyrias. In this study, we identified the mouse harderian gland as a novel expression site of Bcrp1. Because of its pronounced role in porphyrin secretion, the harderian gland presents a useful tool to study the mechanism of Bcrp1-related protoporphyria and transport of porphyrins. Bcrp1−/− harderian gland displayed a highly increased accumulation of PPIX glycoconjugates, and a similar shift was seen in Bcrp1−/− liver. Tear- and hepatobiliary excretion data suggest that Bcrp1 controls intracellular levels of PPIX by mediating high affinity transport of its glycoconjugates and possibly low-affinity transport of unconjugated PPIX. This mechanism may allow cells to prevent or reduce cytotoxicity of PPIX under excess conditions, without spillage under physiological conditions where PPIX is needed.

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Accumulation of protoporphyrin IX from delta-aminolevulinic acid in bovine skin fibroblasts with hereditary erythropoietic protoporphyria. A gene-dosage effect.

Journal of Experimental Medicine ◽

10.1084/jem.153.5.1094 ◽

1981 ◽

Vol 153 (5) ◽

pp. 1094-1101 ◽

Cited By ~ 13

Author(s):

S Sassa ◽

S Schwartz ◽

G Ruth

Keyword(s):

Aminolevulinic Acid ◽

Clinical Symptoms ◽

Gene Dosage ◽

Protoporphyrin Ix ◽

Skin Fibroblasts ◽

Erythropoietic Protoporphyria ◽

Gene Dosage Effect ◽

Cultured Fibroblasts ◽

Clinically Normal ◽

Stimulation Of

Bovine skin fibroblasts accumulated protoporphyrin IX when incubated in culture with the porphyrin-heme precursor, delta-aminolevulinic acid (ALA). Fibroblasts from cattle homozygous for erythropoietic protoporphyria (EPP) and with the clinical symptoms of the disease accumulated approximately sixfold greater amounts of protoporphyrin IX than cells from normal control animals. Cells from obligatory heterozygous animals, which are clinically normal, accumulated an intermediate level of protoporphyrin IX. When these cells were incubated with ALA and CaMg EDTA, all types of cells accumulated approximately the same amount of protoporphyrin IX (approximately 500 nmol/mg protein), suggesting that ferrochelatase activity was equally low after inhibition by treatment with CaMg EDTA in all cells. Thus the ratio of protoporphyrin IX accumulation from ALA in cultures treated with CaMg EDTA compared with controls treated with ALA alone was greatest in normal cells, least in EPP cells, and intermediate in the heterozygote cells. These findings suggest that the amount of protoporphyrin IX accumulation from ALA reflects the extent of deficiency of ferrochelatase and is proportional to the dosage of abnormal EPP gene in cultured fibroblasts. Similarly, stimulation of porphyrin accumulation by CaMg EDTA reflects diminished ferrochelatase activity in these cells. Thus, the results of this study demonstrate the usefulness of estimating protoporphyrin IX formation from ALA for the detection of an EPP gene defect in cultured bovine skin fibroblasts.

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The Ratio of Erythrocyte Zinc-Protoporphyrin to Protoporphyrin IX in Disease and its Significance in the Mechanism of Lead Toxicity on Haem Synthesis

Annals of Clinical Biochemistry International Journal of Laboratory Medicine ◽

10.1177/000456329803500313 ◽

1998 ◽

Vol 35 (3) ◽

pp. 422-426 ◽

Cited By ~ 4

Author(s):

Joanna C Nelson ◽

Marie Westwood ◽

K R Allen ◽

K E Newton ◽

J H Barth

Keyword(s):

Iron Deficiency ◽

Protoporphyrin Ix ◽

Lead Toxicity ◽

Normal Subjects ◽

Zinc Protoporphyrin ◽

Mechanism Of Formation ◽

Erythropoietic Protoporphyria ◽

Iron Deficient ◽

Significant Difference ◽

Exposed Workers

Protoporphyrin and zinc-protoporphyrin were measured in the erythrocytes of normal subjects, workers exposed to lead and patients with iron deficiency and erythropoietic protoporphyria (EPP). Results showed significantly higher levels of zinc-protoporphyrin in the lead-exposed workers ( P < 0·0001), patients with iron deficiency ( P < 0·0001) and EPP patients ( P < 0·001) compared with normal subjects. The lead-exposed workers showed the highest levels of zinc-protoporphyrin, which were significantly greater than both the iron-deficient and EPP patients ( P < 0·0001). They also showed a higher ratio of zinc-protoporphyrin to free protoporphyrin compared with normal subjects ( P < 0·0001) but no significant difference in this ratio was found when compared with iron-deficient patients ( P = 0·1). These results are discussed in light of the controversy concerning the mechanism of formation of zinc-protoporphyrin in lead exposure.

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Increased expression of the Abcg2 transporter during erythroid maturation plays a role in decreasing cellular protoporphyrin IX levels

Blood ◽

10.1182/blood-2004-04-1566 ◽

2005 ◽

Vol 105 (6) ◽

pp. 2571-2576 ◽

Cited By ~ 87

Author(s):

Sheng Zhou ◽

Yang Zong ◽

Paul A. Ney ◽

Geeta Nair ◽

Clinton F. Stewart ◽

...

Keyword(s):

Potential Role ◽

Protoporphyrin Ix ◽

Erythroid Differentiation ◽

Genetic Determinant ◽

Erythroid Cells ◽

Erythropoietic Protoporphyria ◽

Hematopoietic Stem ◽

Transporter Family ◽

Erythroid Maturation ◽

Abcg2 Protein

AbstractABCG2/BCRP is a member of the adenosine triphosphate–binding cassette (ABC) transporter family and is expressed in intestine, kidney, and liver, where it modulates the absorption and excretion of xenobiotic compounds. ABCG2 is also expressed in hematopoietic stem cells and erythroid cells; however, little is known regarding its role in hematopoiesis. Abcg2 null mice have increased levels of protoporphyrin IX (PPIX) in erythroid cells, yet the mechanism for this remains uncertain. We have found that Abcg2 mRNA expression was up-regulated in differentiating erythroid cells, coinciding with increased expression of other erythroid-specific genes. This expression pattern was associated with significant amounts of ABCG2 protein on the membrane of mature peripheral blood erythrocytes. Erythroid cells engineered to express ABCG2 had significantly lower intracellular levels of PPIX, suggesting the modulation of PPIX level by ABCG2. This modulating activity was abrogated by treatment with a specific ABCG2 inhibitor, Ko143, implying that PPIX may be a direct substrate for the transporter. Taken together, our results demonstrate that ABCG2 plays a role in regulating PPIX levels during erythroid differentiation and suggest a potential role for ABCG2 as a genetic determinant in erythropoietic protoporphyria.

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Congenital Erythropoietic Protoporphyria

Blood ◽

10.1182/blood.v22.5.532.532 ◽

1963 ◽

Vol 22 (5) ◽

pp. 532-544 ◽

Cited By ~ 11

Author(s):

F. STANLEY PORTER

Keyword(s):

Bone Marrow ◽

Inborn Error ◽

Protoporphyrin Ix ◽

Human Bone ◽

Inborn Error Of Metabolism ◽

Human Bone Marrow ◽

Erythropoietic Protoporphyria ◽

In Vitro Synthesis ◽

Basic Defect

Abstract Investigations into the pathophysiology of erythropoietic protoporphyria suggest that the basic defect is an inborn error of metabolism resulting in the overproduction of protoporphyrin IX by the bone marrow not in response to a failure of heme synthesis. A method is described for evaluating the in vitro synthesis of protoporphyrin and heme by human bone marrow.

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In vitro Assessment of Solar Filters for Erythropoietic Protoporphyria in the Action Spectrum of Protoporphyrin IX

Frontiers in Medicine ◽

10.3389/fmed.2021.796884 ◽

2021 ◽

Vol 8 ◽

Author(s):

Alvise Sernicola ◽

Elena Cama ◽

Maria Guglielmina Pelizzo ◽

Enrico Tessarolo ◽

Annamaria Nicolli ◽

...

Keyword(s):

Absorption Spectrum ◽

Protective Efficacy ◽

Action Spectrum ◽

Protoporphyrin Ix ◽

Erythropoietic Protoporphyria ◽

Protection Factor ◽

Visible Radiation ◽

In Vitro Assessment ◽

Photosensitivity Disorders

Introduction: Subjects with erythropoietic protoporphyria rely on broad-spectrum sunscreens with high sun protection factor, which is not informative on efficacy in the absorption spectrum of protoporphyrin IX, spanning visible radiation and peaking around 408 nm. Photoactivation of protoporphyrin IX is responsible for painful skin photosensitivity in erythropoietic protoporphyria.The authors assessed the protective efficacy of six sunscreens in vitro in the absorption spectrum of protoporphyrin IX.Method: Transmittance measurements were performed in the 300–850 nm wavelengths on samples of six photoprotective products applied to polymethyl methacrylate plates. Porphyrin protection factor was calculated in the 300–700 nm region to provide a measurement for the efficacy of each product based on the action spectrum of protoporphyrin IX.Results: Product A showed the highest porphyrin protection factor among tested products with a median value of 4.22. Product A is a sunscreen containing organic filters, titanium dioxide and synthetic iron oxides, pigmentary grade active ingredients that absorb visible radiation. Other products showed inefficient protection in the visible, with transmittance between 75 and 95% at 500 nm. The low porphyrin protection factor of inorganic filter product B was attributed to particle micronization, as declared by the manufacturer.Conclusion: Adding porphyrin protection factor to sunscreen labeling could help patients with erythropoietic protoporphyria and other photosensitivity disorders identify products tailored on their specific needs. The development of sunscreens providing protection from visible radiation and excellent cosmetical tolerability could improve the lifestyle of patients with erythropoietic protoporphyria.

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