Comprehensive Physiology Wiley Online Library
For Librarians For Authors Editors About

Porphyrin and Heme Metabolism and the Porphyrias

Herbert L. Bonkovsky, Jun‐Tao Guo, Weihong Hou, Ting Li, Tarun Narang, Manish Thapar

10.1002/cphy.c120006

Source: Volume 3, Issue 1, January 2013

Published online: January 2013

Full Article on Wiley Online Library



Abstract

Porphyrins and metalloporphyrins are the key pigments of life on earth as we know it, because they include chlorophyll (a magnesium‐containing metalloporphyrin) and heme (iron protoporphyrin). In eukaryotes, porphyrins and heme are synthesized by a multistep pathway that involves eight enzymes. The first and rate‐controlling step is the formation of delta‐aminolevulinic acid (ALA) from glycine plus succinyl CoA, catalyzed by ALA synthase. Intermediate steps occur in the cytoplasm, with formation of the monopyrrole porphobilinogen and the tetrapyrroles hydroxymethylbilane and a series of porphyrinogens, which are serially decarboxylated. Heme is utilized chiefly for the formation of hemoglobin in erythrocytes, myoglobin in muscle cells, cytochromes P‐450 and mitochondrial cytochromes, and other hemoproteins in hepatocytes. The rate‐controlling step of heme breakdown is catalyzed by heme oxygenase (HMOX), of which there are two isoforms, called HMOX1 and HMOX2. HMOX breaks down heme to form biliverdin, carbon monoxide, and iron. The porphyrias are a group of disorders, mainly inherited, in which there are defects in normal porphyrin and heme synthesis. The cardinal clinical features are cutaneous (due to the skin‐damaging effects of excess deposited porphyrins) or neurovisceral attacks of pain, sometimes with weakness, delirium, seizures, and the like (probably due mainly to neurotoxic effects of ALA). The treatment of choice for the acute hepatic porphyrias is intravenous heme therapy, which repletes a critical regulatory heme pool in hepatocytes and leads to downregulation of hepatic ALA synthase, which is a biochemical hallmark of all forms of acute porphyria in relapse. © 2013 American Physiological Society. Compr Physiol 3:365‐401, 2013.

Comprehensive Physiology offers downloadable PowerPoint presentations of figures for non-profit, educational use, provided the content is not modified and full credit is given to the author and publication.

Download a PowerPoint presentation of all images


Figure 1. Figure 1.

The heme biosynthetic pathway showing major intermediates and enzymatic steps. Adapted from reference (31), used by permission of the author and publisher.
Figure 2. Figure 2.

The heme biosynthetic pathway and aspects of its regulation in hepatocytes. Key roles are played by δ‐aminolevulinic acid synthase‐1 (ALAS1), heme oxygenase 1 (HMOX1), nuclear receptors (NRs), and hydroxymethylbilane synthase (HMBS) [also known as porphobilinogen (PBG) deaminase]. Heme itself downregulates several steps in the synthetic pathway, especially ALA synthase‐1, by down regulating transcription, upregulating mRNA breakdown, blocking uptake into mitochondria, and increasing Lon peptidase 1 breakdown of the mature mitochondrial enzyme. Heme upregulates HMOX1, mainly by increasing its transcription through binding to Bach1, a tonic repressor. HMBS is present in low amounts and becomes rate controlling when ALA synthase‐1 is induced. Fifty percent deficiency of HMBS, the defect in acute intermittent porphyria (AIP), can lead to critical deficiency of heme and uncontrolled induction of ALAS1. Heme administered IV is taken up well by hepatocytes, and can replete heme pools rapidly and correct the defects caused by HMBS and other synthetic enzyme deficiencies.
Figure 3. Figure 3.

The structure and nomenclature of the porphyrin macrocycle according to the Fischer and IUPAC nomenclatures. From reference (31), used by permission of the author and publisher
Figure 4. Figure 4.

Chemical structures of different types of heme. (A) Heme b; (B) Heme c; (C) Heme d; (D) Heme a; and (E) Heme o. The differences between non‐b types of heme and heme b are shown inside the dashed lines.
Figure 5. Figure 5.

Three‐dimensional structures of single‐ and multiheme proteins. (A) Yeast iso‐1‐cytochrome c [PDB: 1YCC (146)]; (B) cytochrome c from rhodothermus marinus [3CP5 (223)], the covalent bonds between heme and the cysteine residues of the protein are shown in circles; (C) cytochrome c nitrite reductase of Wolinella succinogenes [PDB: 1FS7 (80)] with five heme b molecules; (D) thioalkalivibrio nitratireducens cytochrome c nitrite reductase (PDB: 3F29) with eight heme c molecules. For better visualization, the heme molecules in multiheme proteins (C and D) are shown using spacefill while the single heme in A and B is rendered with sticks (red: oxygen; blue: nitrogen; purple: carbon). The images were generated using Pymol (http://www.pymol.org).
Figure 6. Figure 6.

The pathway of physiologic breakdown of heme.
Figure 7. Figure 7.

Role of heme and BACH1 in regulation of expression of the heme oxygenase‐1 gene.
Figure 8. Figure 8.

Summary diagnostic algorithm for the acute porphyrias.
Figure 9. Figure 9.

Effect of intravenous heme on plasma levels of aminolevulinic acid (ALA) and porphobilinogen (PBG) in the first patient so treated. Adapted from reference (47), with permission of the author and publisher.
Figure 10. Figure 10.

Typical cutaneous manifestations of porphyria cutanea tarda (PCT). Cutaneous lesions with bullae, vesicles, and erosions on the dorsum of the hand. From reference (53), used by permission of the authors and publisher.
Figure 11. Figure 11.

Hepatic histopathology in porphyria cutanea tarda (PCT). Fresh unfixed liver fluoresces a bright pink (A) due to excess porphyrins. Typically, there is some degree of iron loading (B) and fatty change and inflammation (C). The latter is often due to alcohol or chronic hepatitis C. Sometimes, cirrhosis and/or hepatocellular carcinoma develop (D). Photomicrographs kindly provided by J.R. Bloomer.
Figure 12. Figure 12.

Pathogenesis of porphyria cutanea tarda. The figure shows a summary of the normal pathway of heme biosynthesis, with emphasis on uroporphyrinogen decarboxylase (UROD) and its inhibition by an oxidation product thought to be derived from uroporphyrinogen. Formation of the inhibitor is thought also to require the action of CYP1A2. Several sites of action of iron are shown, including synergistic induction of ALA synthase 1, increases in oxidative stress [reactive oxygen species (ROS)], induction of heme oxygenase. Alcohol and estrogens also increase ROS and induce δ‐aminolevulinic acid synthase‐1 (ALAS1). Hepatitis C virus (HCV) infection increases ROS and decreases hepcidin production. The latter decrease is due to upregulation of histone deacetylase (HDAC) and ccat enhancer binding protein (CEBP) homology protein (CHOP), which result in decreased binding of CEBP to the hepcidin gene promoter region and thus decreased hepcidin production. Mutations in the HFE, HJV, and/or TfR2 genes also lead to decreased hepcidin production. The decrease in hepcidin leads to increased absorption of iron from the small intestine, leading to further hepatic iron overload and to amplification of the metabolic disarray.
Figure 13. Figure 13.

Clinical presentation of congenital erythropoietic porphyria (CEP). From reference (206), used by permission of the authors and publisher.


Figure 1.

The heme biosynthetic pathway showing major intermediates and enzymatic steps. Adapted from reference (31), used by permission of the author and publisher.



Figure 2.

The heme biosynthetic pathway and aspects of its regulation in hepatocytes. Key roles are played by δ‐aminolevulinic acid synthase‐1 (ALAS1), heme oxygenase 1 (HMOX1), nuclear receptors (NRs), and hydroxymethylbilane synthase (HMBS) [also known as porphobilinogen (PBG) deaminase]. Heme itself downregulates several steps in the synthetic pathway, especially ALA synthase‐1, by down regulating transcription, upregulating mRNA breakdown, blocking uptake into mitochondria, and increasing Lon peptidase 1 breakdown of the mature mitochondrial enzyme. Heme upregulates HMOX1, mainly by increasing its transcription through binding to Bach1, a tonic repressor. HMBS is present in low amounts and becomes rate controlling when ALA synthase‐1 is induced. Fifty percent deficiency of HMBS, the defect in acute intermittent porphyria (AIP), can lead to critical deficiency of heme and uncontrolled induction of ALAS1. Heme administered IV is taken up well by hepatocytes, and can replete heme pools rapidly and correct the defects caused by HMBS and other synthetic enzyme deficiencies.



Figure 3.

The structure and nomenclature of the porphyrin macrocycle according to the Fischer and IUPAC nomenclatures. From reference (31), used by permission of the author and publisher



Figure 4.

Chemical structures of different types of heme. (A) Heme b; (B) Heme c; (C) Heme d; (D) Heme a; and (E) Heme o. The differences between non‐b types of heme and heme b are shown inside the dashed lines.



Figure 5.

Three‐dimensional structures of single‐ and multiheme proteins. (A) Yeast iso‐1‐cytochrome c [PDB: 1YCC (146)]; (B) cytochrome c from rhodothermus marinus [3CP5 (223)], the covalent bonds between heme and the cysteine residues of the protein are shown in circles; (C) cytochrome c nitrite reductase of Wolinella succinogenes [PDB: 1FS7 (80)] with five heme b molecules; (D) thioalkalivibrio nitratireducens cytochrome c nitrite reductase (PDB: 3F29) with eight heme c molecules. For better visualization, the heme molecules in multiheme proteins (C and D) are shown using spacefill while the single heme in A and B is rendered with sticks (red: oxygen; blue: nitrogen; purple: carbon). The images were generated using Pymol (http://www.pymol.org).



Figure 6.

The pathway of physiologic breakdown of heme.



Figure 7.

Role of heme and BACH1 in regulation of expression of the heme oxygenase‐1 gene.



Figure 8.

Summary diagnostic algorithm for the acute porphyrias.



Figure 9.

Effect of intravenous heme on plasma levels of aminolevulinic acid (ALA) and porphobilinogen (PBG) in the first patient so treated. Adapted from reference (47), with permission of the author and publisher.



Figure 10.

Typical cutaneous manifestations of porphyria cutanea tarda (PCT). Cutaneous lesions with bullae, vesicles, and erosions on the dorsum of the hand. From reference (53), used by permission of the authors and publisher.



Figure 11.

Hepatic histopathology in porphyria cutanea tarda (PCT). Fresh unfixed liver fluoresces a bright pink (A) due to excess porphyrins. Typically, there is some degree of iron loading (B) and fatty change and inflammation (C). The latter is often due to alcohol or chronic hepatitis C. Sometimes, cirrhosis and/or hepatocellular carcinoma develop (D). Photomicrographs kindly provided by J.R. Bloomer.



Figure 12.

Pathogenesis of porphyria cutanea tarda. The figure shows a summary of the normal pathway of heme biosynthesis, with emphasis on uroporphyrinogen decarboxylase (UROD) and its inhibition by an oxidation product thought to be derived from uroporphyrinogen. Formation of the inhibitor is thought also to require the action of CYP1A2. Several sites of action of iron are shown, including synergistic induction of ALA synthase 1, increases in oxidative stress [reactive oxygen species (ROS)], induction of heme oxygenase. Alcohol and estrogens also increase ROS and induce δ‐aminolevulinic acid synthase‐1 (ALAS1). Hepatitis C virus (HCV) infection increases ROS and decreases hepcidin production. The latter decrease is due to upregulation of histone deacetylase (HDAC) and ccat enhancer binding protein (CEBP) homology protein (CHOP), which result in decreased binding of CEBP to the hepcidin gene promoter region and thus decreased hepcidin production. Mutations in the HFE, HJV, and/or TfR2 genes also lead to decreased hepcidin production. The decrease in hepcidin leads to increased absorption of iron from the small intestine, leading to further hepatic iron overload and to amplification of the metabolic disarray.



Figure 13.

Clinical presentation of congenital erythropoietic porphyria (CEP). From reference (206), used by permission of the authors and publisher.

References
 1. Abraham NG, Kappas A. Heme oxygenase and the cardiovascular‐renal system. Free Radic Biol Med 39: 1‐25, 2005.
 2. Abraham NG, Kappas A. Pharmacological and clinical aspects of heme oxygenase. Pharmacol Rev 60: 79‐127, 2008.
 3. Alam J, Camhi S, Choi AM. Identification of a second region upstream of the mouse heme oxygenase‐1 gene that functions as a basal level and inducer‐dependent transcription enhancer. J Biol Chem 270: 11977‐11984, 1995.
 4. Alam J, Killeen E, Gong P, Naquin R, Hu B, Stewart D, Ingelfinger JR, Nath KA. Heme activates the heme oxygenase‐1 gene in renal epithelial cells by stabilizing Nrf2. Am J Physiol Renal Physiol 284: F743‐F752, 2003.
 5. Alam J, Stewart D, Touchard C, Boinapally S, Choi AM, Cook JL. Nrf2, a Cap'n'Collar transcription factor, regulates induction of the heme oxygenase‐1 gene. J Biol Chem 274: 26071‐26078, 1999.
 6. Alla V, Bonkovsky HL. Iron in nonhemochromatotic liver disorders. Semin Liver Dis 25: 461‐472, 2005.
 7. Almehmi A, Deliri H, Szego GG, Teague AC, Pfister AK, Martin SA. Porphyria cutanea tarda in a patient with HIV‐infection. W V Med J 101: 19‐21, 2005.
 8. Ambros V. The functions of animal microRNAs. Nature 431: 350‐355, 2004.
 9. Andant C, Puy H, Faivre J, Deybach JC. Acute hepatic porphyrias and primary liver cancer. N Engl J Med 338: 1853‐1854, 1998.
 10. Anderson KE, Bonkovsky HL, Bloomer JR, Shedlofsky SI. Reconstitution of hematin for intravenous infusion. Ann Intern Med 144: 537‐538, 2006.
 11. Anstey AV, Hift RJ. Liver disease in erythropoietic protoporphyria: Insights and implications for management. Gut 56: 1009‐1018, 2007.
 12. Armstrong DK, Sharpe PC, Chambers CR, Whatley SD, Roberts AG, Elder GH. Hepatoerythropoietic porphyria: A missense mutation in the UROD gene is associated with mild disease and an unusual porphyrin excretion pattern. Br J Dermatol 151: 920‐923, 2004.
 13. Arnold WN. Vincent van Gogh: Chemicals, Crises, and Creativity. Berlin, Boston, Basel: Birkhäuser, 1992.
 14. Aziz N, Munro HN. Iron regulates ferritin mRNA translation through a segment of its 5' untranslated region. Proc Natl Acad Sci U S A 84: 8478‐8482, 1987.
 15. Badiu C, Cristofor D, Voicu D, Coculescu M. Diagnostic traps in porphyria: Case report and literature review. Rev Med Chir Soc Med Nat Iasi 108: 584‐591, 2004.
 16. Badminton MN, Elder GH. Molecular mechanisms of dominant expression in porphyria. J Inherit Metab Dis 28: 277‐286, 2005.
 17. Balestrasse KB, Noriega GO, Batlle A, Tomaro ML. Involvement of heme oxygenase as antioxidant defense in soybean nodules. Free Radic Res 39: 145‐151, 2005.
 18. Baranano DE, Rao M, Ferris CD, Snyder SH. Biliverdin reductase: A major physiologic cytoprotectant. Proc Natl Acad Sci U S A 99: 16093‐16098, 2002.
 19. Bartel DP. MicroRNAs: Genomics, biogenesis, mechanism, and function. Cell 116: 281‐297, 2004.
 20. Beale SI. Enzymes of chlorophyll biosynthesis. Photosynth Res 60: 43‐73, 1999.
 21. Beckman JD, Chen C, Nguyen J, Thayanithy V, Subramanian S, Steer CJ, Vercellotti GM. Regulation of heme oxygenase‐1 protein expression by miR‐377 in combination with miR‐217. J Biol Chem 286: 3194‐3202.
 22. Berberat PO, YI AR, Yamashita K, Warny MM, Csizmadia E, Robson SC, Bach FH. Heme oxygenase‐1‐generated biliverdin ameliorates experimental murine colitis. Inflamm Bowel Dis 11: 350‐359, 2005.
 23. Berger H, Goldberg A. Hereditary coproporphyria. Br Med J 2: 85‐88, 1955.
 24. Berk DR, Mallory SB, Keeffe EB, Ahmed A. Dermatologic disorders associated with chronic hepatitis C: Effect of interferon therapy. Clin Gastroenterol Hepatol 5: 142‐151, 2006.
 25. Bissell DM. Treatment of acute hepatic porphyria with hematin. J Hepatol 6: 1‐7, 1988.
 26. Bloomer JR, Bonkovsky HL. The porphyrias. Dis Mon 35: 1‐54, 1989.
 27. Bloomer JR, Hill HD, Kools AM, Straka JG. Heme synthesis in protoporphyria. Curr Probl Dermatol 20: 135‐147, 1991.
 28. Bloomer JR, Pierach CA. Effect of hematin administration to patients with protoporphyria and liver disease. Hepatology 2: 817‐821, 1982.
 29. Bonkovsky HL. Porphyrin and heme metabolism and the porphyrias. In: Zakim D, Boyer T, editors. Hepatology: A Textbook of Liver Disease (1st ed). Philadelphia: Saunders, 1982, pp. 351‐393.
 30. Bonkovsky HL. Mechanism of iron potentiation of hepatic uroporphyria: Studies in cultured chick embryo liver cells. Hepatology 10: 354‐364, 1989.
 31. Bonkovsky HL. Porphyrin and heme metabolism and the porphyrias. In: Zakim D, Boyer T, editors. Hepatology: A Textbook of Liver Disease (2nd ed). Philadelphia: Saunders, 1990, pp. 378‐424.
 32. Bonkovsky HL, Barnard GF. Diagnosis of porphyric syndromes: A practical approach in the era of molecular biology. Semin Liver Dis 18: 57‐65, 1998.
 33. Bonkovsky HL, Cable EE, Cable JW, Donohue SE, White EC, Greene YJ, Lambrecht RW, Srivastava KK, Arnold WN. Porphyrogenic properties of the terpenes camphor, pinene, and thujone (with a note on historic implications for absinthe and the illness of Vincent van Gogh). Biochem Pharmacol 43: 2359‐2368, 1992.
 34. Bonkovsky HL, Elbirt, K. Heme oxygenase: Its regulation and role. In: Cutler RG, Rodriguez, H, editors. Oxidative Stress and Aging, River Edge, NJ: World Scientific, 2002, pp. 699‐706.
 35. Bonkovsky HL, Healey JF, Lourie AN, Gerron GG. Intravenous heme‐albumin in acute intermittent porphyria: Evidence for repletion of hepatic hemoproteins and regulatory heme pools. Am J Gastroenterol 86: 1050‐1056, 1991.
 36. Bonkovsky HL, Healey JF, Pohl J. Purification and characterization of heme oxygenase from chick liver. Comparison of the avian and mammalian enzymes. Eur J Biochem 189: 155‐166, 1990.
 37. Bonkovsky HL, Lambrecht RW. Hemochromatosis, iron overload, and porphyria cutanea tarda. In: Barton JC, Edwards CQ, editors. Hemochromatosis‐Genetics, Pathophysiology, Diagnosis, and Treatment, Cambridge, UK: Cambridge University Press, 2000, pp. 453‐467.
 38. Bonkovsky HL, Lambrecht RW. Iron‐induced liver injury. Clin Liver Dis 4: 409‐429, vi‐vii, 2000.
 39. Bonkovsky HL, Lambrecht RW, Naishadham D. Genetic variations in heme oxygenase‐1 and chronic hepatitis. Hepatology 52: 400‐401.
 40. Bonkovsky HL, Lambrecht RW, Shan Y. Iron as a co‐morbid factor in nonhemochromatotic liver disease. Alcohol 30: 137‐144, 2003.
 41. Bonkovsky HL, Naishadham D, Lambrecht RW, Chung RT, Hoefs JC, Nash SR, Rogers TE, Banner BF, Sterling RK, Donovan JA, Fontana RJ, Di Bisceglie AM, Ghany MG, Morishima C. Roles of iron and HFE mutations on severity and response to therapy during retreatment of advanced chronic hepatitis C. Gastroenterology 131: 1440‐1451, 2006.
 42. Bonkovsky HL, Poh‐Fitzpatrick M, Pimstone N, Obando J, Di Bisceglie A, Tattrie C, Tortorelli K, LeClair P, Mercurio MG, Lambrecht RW. Porphyria cutanea tarda, hepatitis C, and HFE gene mutations in North America. Hepatology 27: 1661‐1669, 1998.
 43. Bonkovsky HL, Schned AR. Fatal liver failure in protoporphyria. Synergism between ethanol excess and the genetic defect. Gastroenterology 90: 191‐201, 1986.
 44. Bonkovsky HLT, M. Porphyria Philadelphia, PA: Elsevier Health, 2008.
 45. Bonkowsky HL, Bloomer JR, Ebert PS, Mahoney MJ. Heme synthetase deficiency in human protoporphyria. Demonstration of the defect in liver and cultured skin fibroblasts. J Clin Invest 56: 1139‐1148, 1975.
 46. Bonkowsky HL, Schady W. Neurologic manifestations of acute porphyria. Semin Liver Dis 2: 108‐124, 1982.
 47. Bonkowsky HL, Tschudy DP, Collins A, Doherty J, Bossenmaier I, Cardinal R, Watson CJ. Repression of the overproduction of porphyrin precursors in acute intermittent porphyria by intravenous infusions of hematin. Proc Natl Acad Sci U S A 68: 2725‐2729, 1971.
 48. Bowman SE, Bren KL. The chemistry and biochemistry of heme c: Functional bases for covalent attachment. Nat Prod Rep 25: 1118‐1130, 2008.
 49. Brodie MJ, Thompson GG, Moore MR, Beattie AD, Goldberg A. Hereditary coproporphyria. Demonstration of the abnormalities in haem biosynthesis in peripheral blood. Q J Med 46: 229‐241, 1977.
 50. Brouard S, Otterbein LE, Anrather J, Tobiasch E, Bach FH, Choi AM, Soares MP. Carbon monoxide generated by heme oxygenase 1 suppresses endothelial cell apoptosis. J Exp Med 192: 1015‐1026, 2000.
 51. Burger D, Xiang F, Hammoud L, Lu X, Feng Q. Role of heme oxygenase‐1 in the cardioprotective effects of erythropoietin during myocardial ischemia and reperfusion. Am J Physiol Heart Circ Physiol 296: H84‐H93, 2009.
 52. Caballes FR, Bonkovsky HL. Gastroenterology and hepatology: Chronic porphyrias. In: Bacon B, Spechler S, editors. Decision Support in Medicine (in press), 2012.
 53. Caballes FR, Sendi H, Bonkovsky HL. Hepatitis C, porphyria cutanea tarda, and liver iron: An update. Liver Intl 32: 880‐893, 2012.
 54. Casanova‐Gonzalez MJ, Trapero‐Marugan M, Jones EA, Moreno‐Otero R. Liver disease and erythropoietic protoporphyria: A concise review. World J Gastroenterol 16: 4526‐4531, 2010.
 55. Cavanagh JB, Mellick RS. On the nature of the peripheral nerve lesions associated with acute intermittent porphyria. J Neurol Neurosurg Psychiatry 28: 320‐327, 1965.
 56. Chemmanur AT, Bonkovsky HL. Hepatic porphyrias: Diagnosis and management. Clin Liver Dis 8: 807‐838, viii, 2004.
 57. Chen FP, Risheg H, Liu Y, Bloomer J. Ferrochelatase gene mutations in erythropoietic protoporphyria: Focus on liver disease. Cell Mol Biol (Noisy‐le‐grand) 48: 83‐89, 2002.
 58. Chen YH, Lin SJ, Lin MW, Tsai HL, Kuo SS, Chen JW, Charng MJ, Wu TC, Chen LC, Ding YA, Pan WH, Jou YS, Chau LY. Microsatellite polymorphism in promoter of heme oxygenase‐1 gene is associated with susceptibility to coronary artery disease in type 2 diabetic patients. Hum Genet 111: 1‐8, 2002.
 59. Chudley AE, Haworth JC. Genetic landmarks through philately–porphyria and its effect on world history. Clin Genet 55: 85‐87, 1999.
 60. Connon JJ, Turkington V. Hereditary coproporphyria. Lancet 2: 263‐264, 1968.
 61. Cooper CL, Stob CM, Jones MA, Lash TD. Metabolism of pentacarboxylate porphyrinogens by highly purified human coproporphyrinogen oxidase: Further evidence for the existence of an abnormal pathway for heme biosynthesis. Bioorg Med Chem 13: 6244‐6251, 2005.
 62. Cox TC, Bawden MJ, Martin A, May BK. Human erythroid 5‐aminolevulinate synthase: Promoter analysis and identification of an iron‐responsive element in the mRNA. EMBO J 10: 1891‐1902, 1991.
 63. Cox TM, Alexander GJ, Sarkany RP. Protoporphyria. Semin Liver Dis 18: 85‐93, 1998.
 64. Cruz‐Rojo J, Fontanellas A, Moran‐Jimenez MJ, Navarro‐Ordonez S, Garcia‐Bravo M, Mendez M, Munoz‐Rivero MC, de Salamanca RE. Precipitating/aggravating factors of porphyria cutanea tarda in Spanish patients. Cell Mol Biol (Noisy‐le‐grand) 48: 845‐852, 2002.
 65. Dailey TA, Woodruff JH, Dailey HA. Examination of mitochondrial protein targeting of haem synthetic enzymes: In vivo identification of three functional haem‐responsive motifs in 5‐aminolaevulinate synthase. Biochem J 386: 381‐386, 2005.
 66. Dandekar T, Stripecke R, Gray NK, Goossen B, Constable A, Johansson HE, Hentze MW. Identification of a novel iron‐responsive element in murine and human erythroid delta‐aminolevulinic acid synthase mRNA. EMBO J 10: 1903‐1909, 1991.
 67. Daniell WE, Stockbridge HL, Labbe RF, Woods JS, Anderson KE, Bissell DM, Bloomer JR, Ellefson RD, Moore MR, Pierach CA, Schreiber WE, Tefferi A, Franklin GM. Environmental chemical exposures and disturbances of heme synthesis. Environ Health Perspect 105 (Suppl 1): 37‐53, 1997.
 68. Danton M, Lim CK. Porphomethene inhibitor of uroporphyrinogen decarboxylase: Analysis by high‐performance liquid chromatography/electrospray ionization tandem mass spectrometry. Biomed Chromatogr 21: 661‐663, 2007.
 69. Dar FS, Asai K, Haque AR, Cherian T, Rela M, Heaton N. Liver transplantation for acute intermittent porphyria: A viable treatment? Hepatobiliary Pancreat Dis Int 9: 93‐96, 2010.
 70. DeLeo VA, Poh‐Fitzpatrick M, Mathews‐Roth M, Harber LC. Erythropoietic protoporphyria. 10 years experience. Am J Med 60: 8‐22, 1976.
 71. Desai TK, Jamil LH, Balasubramaniam M, Koff R, Bonkovsky HL. Phlebotomy improves therapeutic response to interferon in patients with chronic hepatitis C: A meta‐analysis of six prospective randomized controlled trials. Dig Dis Sci 53: 815‐822, 2008.
 72. Do KD, Banner BF, Katz E, Szymanski IO, Bonkovsky HL. Benefits of chronic plasmapheresis and intravenous heme‐albumin in erythropoietic protoporphyria after orthotopic liver transplantation. Transplantation 73: 469‐472, 2002.
 73. Dobriner K. Simultaneous excretion of coproporphyrin I and III in a case of chronic porphyria. Proc Soc Exp Biol Med 35: 175, 1936.
 74. Doss M, von Tiepermann R, Schneider J, Schmid H. New type of hepatic porphyria with porphobilinogen synthase defect and intermittent acute clinical manifestation. Klin Wochenschr 57: 1123‐1127, 1979.
 75. Dowman JK, Gunson BK, Bramhall S, Badminton MN, Newsome PN. Liver transplantation from donors with acute intermittent porphyria. Ann Intern Med 154: 571‐572, 2011.
 76. Dowman JK, Gunson BK, Mirza DF, Bramhall SR, Badminton MN, Newsome PN. Liver transplantation for acute intermittent porphyria is complicated by a high rate of hepatic artery thrombosis. Liver Transpl 18: 195‐200, 2012.
 77. Drew PD, Ades IZ. Regulation of the stability of chicken embryo liver delta‐aminolevulinate synthase mRNA by hemin. Biochem Biophys Res Commun 162: 102‐107, 1989.
 78. Dupuis‐Girod S, Akkari V, Ged C, Galambrun C, Kebaïli K, Deybach J‐C, Claudy A, Geburher L, Philippe N, de Verneuil H, Bertrand Y. Successful match‐unrelated donor bone marrow transplantation for congenital erythropoietic porphyria (Günther disease). Eur J Pediatr 164: 104‐107, 2005.
 79. Eefsen M, Rasmussen A, Wulf HC, Brock A, Hansen BA. Erythropoietic protoporphyria and pretransplantation treatment with nonbiological liver assist devices. Liver Transpl 13: 655‐657, 2007.
 80. Einsle O, Stach P, Messerschmidt A, Simon J, Kroger A, Huber R, Kroneck PM. Cytochrome c nitrite reductase from Wolinella succinogenes. Structure at 1.6 A resolution, inhibitor binding, and heme‐packing motifs. J Biol Chem 275: 39608‐39616, 2000.
 81. Elbirt KK, Bonkovsky HL. Heme oxygenase: Recent advances in understanding its regulation and role. Proc Assoc Am Phys 111: 438‐447, 1999.
 82. Elbirt KK, Whitmarsh AJ, Davis RJ, Bonkovsky HL. Mechanism of sodium arsenite‐mediated induction of heme oxygenase‐1 in hepatoma cells. Role of mitogen‐activated protein kinases. J Biol Chem 273: 8922‐8931, 1998.
 83. Elder GH. The cutaneous porphyrias. Semin Dermatol 9: 63‐69, 1990.
 84. Elder GH. Porphyria cutanea tarda. Semin Liver Dis 18: 67‐75, 1998.
 85. Elder GH, Smith SG, Herrero C, Lecha M, Mascaro JM, Muniesa AM, Czarnecki DB, Brenan J, Poulos V, DE Salamanca RE. Hepatoerythropoietic porphyria: A new uroporphyrinogen decarboxylase defect or homozygous porphyria cutanea tarda? Lancet 1: 916‐919, 1981.
 86. Elich TD, McDonagh AF, Palma LA, Lagarias JC. Phytochrome chromophore biosynthesis. Treatment of tetrapyrrole‐deficient Avena explants with natural and non‐natural bilatrienes leads to formation of spectrally active holoproteins. J Biol Chem 264: 183‐189, 1989.
 87. Evans JP, Niemevz F, Buldain G, de Montellano PO. Isoporphyrin intermediate in heme oxygenase catalysis. Oxidation of alpha‐meso‐phenylheme. J Biol Chem 283: 19530‐19539, 2008.
 88. Ewing JF, Maines MD. Histochemical localization of heme oxygenase‐2 protein and mRNA expression in rat brain. Brain Res Brain Res Protoc 1: 165‐174, 1997.
 89. Falk JE. Porphyrins and Metalloporphyrins. Amsterdam: Elsevier, 1964.
 90. Faller M, Matsunaga M, Yin S, Loo JA, Guo F. Heme is involved in microRNA processing. Nat Struct Mol Biol 14: 23‐29, 2007.
 91. Fang J, Sawa T, Akaike T, Akuta T, Sahoo SK, Khaled G, Hamada A, Maeda H. In vivo antitumor activity of pegylated zinc protoporphyrin: Targeted inhibition of heme oxygenase in solid tumor. Cancer Res 63: 3567‐3574, 2003.
 92. Felsher BF, Kushner JP. Hepatic siderosis and porphyria cutanea tarda: Relation of iron excess to the metabolic defect. Semin Hematol 14: 243‐251, 1977.
 93. Felsher BF, Redeker AG. Acute intermittent porphyria: Effect of diet and griseofulvin. Medicine (Baltimore) 46: 217‐223, 1967.
 94. Foran SE, Abel G. Guide to porphyrias. A historical and clinical perspective. Am J Clin Pathol 119 (Suppl): S86‐S93, 2003.
 95. Fracanzani AL, Taioli E, Sampietro M, Fatta E, Bertelli C, Fiorelli G, Fargion S. Liver cancer risk is increased in patients with porphyria cutanea tarda in comparison to matched control patients with chronic liver disease. J Hepatol 35: 498‐503, 2001.
 96. Fraser DJ, Podvinec M, Kaufmann MR, Meyer UA. Drugs mediate the transcriptional activation of the 5‐aminolevulinic acid synthase (ALAS1) gene via the chicken xenobiotic‐sensing nuclear receptor (CXR). J Biol Chem 277: 34717‐34726, 2002.
 97. Fraser DJ, Zumsteg A, Meyer UA. Nuclear receptors constitutive androstane receptor and pregnane X receptor activate a drug‐responsive enhancer of the murine 5‐aminolevulinic acid synthase gene. J Biol Chem 278: 39392‐39401, 2003.
 98. Freesemann A, Frank M, Sieg I, Doss MO. Treatment of porphyria cutanea tarda by the effect of chloroquine on the liver. Skin Pharmacol 8: 156‐161, 1995.
 99. Fritsch C, Bolsen K, Ruzicka T, Goerz G. Congenital erythropoietic porphyria. J Am Acad Dermatol 36: 594‐610, 1997.
 100. Gocmen A, Peters HA, Cripps DJ, Bryan GT, Morris CR. Hexachlorobenzene episode in Turkey. Biomed Environ Sci 2: 36‐43, 1989.
 101. Goldberg A. Acute intermittent porphyria: A study of 50 cases. Q J Med 28: 183‐209, 1959.
 102. Goldberg A, Rimington C, Lochhead AC. Hereditary coproporphyria. Lancet 1: 632‐636, 1967.
 103. Gonzalez‐Arriaza HL, Bostwick JM. Acute porphyrias: A case report and review. AJ Psychiatry 160: 450‐459, 2003.
 104. Gorchein A, Foster GR. Liver failure in protoporphyria: Long‐term treatment with oral charcoal. Hepatology 29: 995‐996, 1999.
 105. Gotoh S, Nakamura T, Kataoka T, Taketani S. Egr‐1 regulates the transcriptional repression of mouse delta‐aminolevulinic acid synthase 1 by heme. Gene 472: 28‐36, 2011.
 106. Gottwein E, Mukherjee N, Sachse C, Frenzel C, Majoros WH, Chi JT, Braich R, Manoharan M, Soutschek J, Ohler U, Cullen BR. A viral microRNA functions as an orthologue of cellular miR‐155. Nature 450: 1096‐1099, 2007.
 107. Gouya L, Martin‐Schmitt C, Robreau AM, Austerlitz F, da Silva V, Brun P, Simonin S, Lyoumi S, Grandchamp B, Beaumont C, Puy H, Deybach JC. Contribution of a common single‐nucleotide polymorphism to the genetic predisposition for erythropoietic protoporphyria. Am J Hum Genet 78: 2‐14, 2006.
 108. Hahn M, Bonkovsky HL. Disorders of porphyrin metabolism. In: Wu G, Israel J, editors. Diseases of the Liver and Bile Ducts: A Practical Guide to Diagnosis and Treatment (1st ed). Totowa, NJ: Humana Press, 1998, pp. 249‐272.
 109. Handschin C, Lin J, Rhee J, Peyer AK, Chin S, Wu PH, Meyer UA, Spiegelman BM. Nutritional regulation of hepatic heme biosynthesis and porphyria through PGC‐1alpha. Cell 122: 505‐515, 2005.
 110. Harms J, Lautenschlager S, Minder CE, Minder EI. An alpha‐melanocyte‐stimulating hormone analogue in erythropoietic protoporphyria. N Engl J Med 360: 306‐307, 2009.
 111. Harms JH, Lautenschlager S, Minder CE, Minder EI. Mitigating photosensitivity of erythropoietic protoporphyria patients by an agonistic analog of alpha‐melanocyte stimulating hormone. Photochem Photobiol 85: 1434‐1439, 2009.
 112. Hift RJ, Corrigall AV, Hancock V, Kannemeyer J, Kirsch RE, Meissner PN. Porphyria cutanea tarda: The etiological importance of mutations in the HFE gene and viral infection is population‐dependent. Cell Mol Biol (Noisy‐le‐grand) 48: 853‐859, 2002.
 113. Hift RJ, Peters TJ, Meissner PN. A review of the clinical presentation, natural history and inheritance of variegate porphyria: Its implausibility as the source of the 'Royal Malady'. J Clin Pathol, 2011.
 114. Holme SA, Anstey AV, Finlay AY, Elder GH, Badminton MN. Erythropoietic protoporphyria in the U.K.: clinical features and effect on quality of life. Br J Dermatol 155: 574‐581, 2006.
 115. Hou W, Shan Y, Zheng J, Lambrecht RW, Donohue SE, Bonkovsky HL. Zinc mesoporphyrin induces rapid and marked degradation of the transcription factor Bach1 and up‐regulates HO‐1. Biochim Biophys Acta 1779: 195‐203, 2008.
 116. Hou W, Tian Q, Zheng J, Bonkovsky HL. MicroRNA‐196 represses Bach1 protein and hepatitis C virus gene expression in human hepatoma cells expressing hepatitis C viral proteins. Hepatology 51: 1494‐1504.
 117. Jeans JB, Savik K, Gross CR, Weimer MK, Bossenmaier IC, Pierach CA, Bloomer JR. Mortality in patients with acute intermittent porphyria requiring hospitalization: A United States case series. Am J Med Genet 65: 269‐273, 1996.
 118. Kaasik K, Lee CC. Reciprocal regulation of haem biosynthesis and the circadian clock in mammals. Nature 430: 467‐471, 2004.
 119. Kaneda H, Ohno M, Taguchi J, Togo M, Hashimoto H, Ogasawara K, Aizawa T, Ishizaka N, Nagai R. Heme oxygenase‐1 gene promoter polymorphism is associated with coronary artery disease in Japanese patients with coronary risk factors. Arterioscler Thromb Vasc Biol 22: 1680‐1685, 2002.
 120. Kapitulnik J, Maines MD. Pleiotropic functions of biliverdin reductase: Cellular signaling and generation of cytoprotective and cytotoxic bilirubin. Trends Pharmacol Sci 30: 129‐137, 2009.
 121. Katori M, Busuttil RW, Kupiec‐Weglinski JW. Heme oxygenase‐1 system in organ transplantation. Transplantation 74: 905‐912, 2002.
 122. Kauppinen R, Mustajoki P. Prognosis of acute porphyria: Occurrence of acute attacks, precipitating factors, and associated diseases. Medicine (Baltimore) 71: 1‐13, 1992.
 123. Koeller DM, Casey JL, Hentze MW, Gerhardt EM, Chan LN, Klausner RD, Harford JB. A cytosolic protein binds to structural elements within the iron regulatory region of the transferrin receptor mRNA. Proc Natl Acad Sci U S A 86: 3574‐3578, 1989.
 124. Kondo M, Yano Y, Shirataka M, Urata G, Sassa S. Porphyrias in Japan: Compilation of all cases reported through 2002. Int J Hematol 79: 448‐456, 2004.
 125. Kostler E, Wollina U. Therapy of porphyria cutanea tarda. Expert Opin Pharmacother 6: 377‐383, 2005.
 126. Kutty RK, Maines MD. Purification and characterization of biliverdin reductase from rat liver. J Biol Chem 256: 3956‐3962, 1981.
 127. Lambrecht RW, Bonkovsky HL. Hemochromatosis and porphyria. Semin Gastrointest Dis 13: 109‐119, 2002.
 128. Lambrecht RW, Fernandez, M, Shan, Y, Bonkovsky, H. L. Heme oxygenase and carbon monoxide in cirrhosis and portal hypertension. In: Ascites and Renal Dysfunction in Liver Disease (2nd ed). Oxford: Blackwell Science, 2005.
 129. Lambrecht RW, Jacobs JM, Sinclair PR, Sinclair JF. Inhibition of uroporphyrinogen decarboxylase activity. The role of cytochrome P‐450‐mediated uroporphyrinogen oxidation. Biochem J 269: 437‐441, 1990.
 130. Lambrecht RW, Sterling RK, Naishadham D, Stoddard AM, Rogers T, Morishima C, Morgan TR, Bonkovsky HL. Iron levels in hepatocytes and portal tract cells predict progression and outcomes of patients with advanced chronic hepatitis C. Gastroenterology 140: 1490‐1500 e1493, 2011.
 131. Lambrecht RW, Thapar M, Bonkovsky HL. Genetic aspects of porphyria cutanea tarda. Semin Liver Dis 27: 99‐108, 2007.
 132. Lamola AA, Joselow M, Yamane T. Zinc protoporphyrin (ZPP): A simple, sensitive fluorometric screening test for lead poisoning. Clin Chem 21: 93‐97, 1975.
 133. Lamola AA, Piomelli S, Poh‐Fitzpatrick MG, Yamane T, Harber LC. Erythropoietic protoporphyria and lead intoxication: The molecular basis for difference in cutaneous photosensitivity. II. Different binding of erythrocyte protoporphyrin to hemoglobin. J Clin Invest 56: 1528‐1535, 1975.
 134. Lamon JM, Frykholm BC, Hess RA, Tschudy DP. Hematin therapy for acute porphyria. Medicine (Baltimore) 58: 252‐269, 1979.
 135. Lathrop JT, Timko MP. Regulation by heme of mitochondrial protein transport through a conserved amino acid motif. Science 259: 522‐525, 1993.
 136. Lee JS, Anvret M. Identification of the most common mutation within the porphobilinogen deaminase gene in Swedish patients with acute intermittent porphyria. Proc Natl Acad Sci U S A 88: 10912‐10915, 1991.
 137. Lee RG, Avner DL, Berenson MM. Structure‐function relationships of protoporphyrin‐induced liver injury. Arch Pathol Lab Med 108: 744‐746, 1984.
 138. Lerner‐Marmarosh N, Shen J, Torno MD, Kravets A, Hu Z, Maines MD. Human biliverdin reductase: A member of the insulin receptor substrate family with serine/threonine/tyrosine kinase activity. Proc Natl Acad Sci U S A 102: 7109‐7114, 2005.
 139. Li T, Bonkovsky HL, Guo JT. Structural analysis of heme proteins: Implications for design and prediction. BMC Struct Biol 11: 13, 2011.
 140. Lim CK, Peters TJ. Urine and faecal porphyrin profiles by reversed‐phase high‐performance liquid chromatography in the porphyrias. Clin Chim Acta 139: 55‐63, 1984.
 141. Lip GY, McColl KE, Goldberg A, Moore MR. Smoking and recurrent attacks of acute intermittent porphyria. BMJ 302: 507, 1991.
 142. Lock G, Holstege A, Mueller AR, Christe W, Doss MO, Scholmerich J, Neuhaus P. Liver failure in erythropoietic protoporphyria associated with choledocholithiasis and severe post‐transplantation polyneuropathy. Liver 16: 211‐217, 1996.
 143. Lockwood WH, Poulos V, Rossi E, Curnow DH. Rapid procedure for fecal porphyrin assay. Clin Chem 31: 1163‐1167, 1985.
 144. Loftus LS, Arnold WN. Vincent van Gogh's illness: Acute intermittent porphyria? BMJ 303: 1589‐1591, 1991.
 145. Longas MO, Poh‐Fitzpatrick MB. A tightly bound protein‐porphyrin complex isolated from the plasma of a patient with variegate porphyria. Clin Chim Acta 118: 219‐228, 1982.
 146. Louie GV, Brayer GD. High‐resolution refinement of yeast iso‐1‐cytochrome c and comparisons with other eukaryotic cytochromes c. J Mol Biol 214: 527‐555, 1990.
 147. Lu TH, Shan Y, Pepe J, Lambrecht RW, Bonkovsky HL. Upstream regulatory elements in chick heme oxygenase‐1 promoter: A study in primary cultures of chick embryo liver cells. Mol Cell Biochem 209: 17‐27, 2000.
 148. Macalpine I, Hunter R. George III and the Mad Business. London: Allen Lane, 1969.
 149. Macalpine I, Hunter R. Porphyria and King George 3rd. Sci Am 221: 38‐46, 1969.
 150. MacDonald DM, Germain D, Perrot H. The histopathology and ultrastructure of liver disease in erythropoietic protoporphyria. Br J Dermatol 104: 7‐17, 1981.
 151. Magnus IA, Jarrett A, Prankerd TA, Rimington C. Erythropoietic protoporphyria. A new porphyria syndrome with solar urticaria due to protoporphyrinaemia. Lancet 2: 448‐451, 1961.
 152. Maines MD. The heme oxygenase system: A regulator of second messenger gases. Annu Rev Pharmacol Toxicol 37: 517‐554, 1997.
 153. Maines MD. New insights into biliverdin reductase functions: Linking heme metabolism to cell signaling. Physiology (Bethesda) 20: 382‐389, 2005.
 154. Maines MD, Trakshel GM, Kutty RK. Characterization of two constitutive forms of rat liver microsomal heme oxygenase. Only one molecular species of the enzyme is inducible. J Biol Chem 261: 411‐419, 1986.
 155. Maruno M, Furuyama K, Akagi R, Horie Y, Meguro K, Garbaczewski L, Chiorazzi N, Doss MO, Hassoun A, Mercelis R, Verstraeten L, Harper P, Floderus Y, Thunell S, Sassa S. Highly heterogeneous nature of delta‐aminolevulinate dehydratase (ALAD) deficiencies in ALAD porphyria. Blood 97: 2972‐2978, 2001.
 156. Mathews‐Roth MM. The consequences of not diagnosing erythropoietic protoporphyria. Arch Dermatol 116: 407, 1980.
 157. Mathews‐Roth MM, Pathak MA, Fitzpatrick TB, Harber LH, Kass EH. Beta carotene therapy for erythropoietic protoporphyria and other photosensitivity diseases. Arch Dermatol 113: 1229‐1232, 1977.
 158. Mathews‐Roth MM, Rosner B. Long‐term treatment of erythropoietic protoporphyria with cysteine. Photodermatol Photoimmunol Photomed 18: 307‐309, 2002.
 159. May BK, Dogra SC, Sadlon TJ, Bhasker CR, Cox TC, Bottomley SS. Molecular regulation of heme biosynthesis in higher vertebrates. Prog Nucleic Acid Res Mol Biol 51: 1‐51, 1995.
 160. McCullough AJ, Barron D, Mullen KD, Petrelli M, Park MC, Mukhtar H, Bickers DR. Fecal protoporphyrin excretion in erythropoietic protoporphyria: Effect of cholestyramine and bile acid feeding. Gastroenterology 94: 177‐181, 1988.
 161. McGuire BM, Bonkovsky HL, Carithers RL, Jr, Chung RT, Goldstein LI, Lake JR, Lok AS, Potter CJ, Rand E, Voigt MD, Davis PR, Bloomer JR. Liver transplantation for erythropoietic protoporphyria liver disease. Liver Transpl 11: 1590‐1596, 2005.
 162. Meguro K, Fujita H, Ishida N, Akagi R, Kurihara T, Galbraith RA, Kappas A, Zabriskie JB, Toback AC, Harber LC, Sassa S. Molecular defects of uroporphyrinogen decarboxylase in a patient with mild hepatoerythropoietic porphyria. J Invest Dermatol 102: 681‐685, 1994.
 163. Mercelis R, Hassoun A, Verstraeten L, De Bock R, Martin JJ. Porphyric neuropathy and hereditary delta‐aminolevulinic acid dehydratase deficiency in an adult. J Neurol Sci 95: 39‐47, 1990.
 164. Miralem T, Hu Z, Torno MD, Lelli KM, Maines MD. Small interference RNA‐mediated gene silencing of human biliverdin reductase, but not that of heme oxygenase‐1, attenuates arsenite‐mediated induction of the oxygenase and increases apoptosis in 293A kidney cells. J Biol Chem 280: 17084‐17092, 2005.
 165. Mor Z, Caspi E. Cutaneous complications of hormonal replacement therapy. Clin Dermatol 15: 147‐154, 1997.
 166. Moran MJ, Fontanellas A, Brudieux E, Hombrados I, de Ledinghen V, Couzigou P, de Verneuil H, De Salamanca RE. Hepatic uroporphyrinogen decarboxylase activity in porphyria cutanea tarda patients: The influence of virus C infection. Hepatology 27: 584‐589, 1998.
 167. Mukerji SK. Haem biosynthesis and human porphyria cutanea tarda: Effects of alcohol intake. Indian J Exp Biol 38: 635‐642, 2000.
 168. Muley SA, Midani HA, Rank JM, Carithers R, Parry GJ. Neuropathy in erythropoietic protoporphyrias. Neurology 51: 262‐265, 1998.
 169. Munakata H, Sun JY, Yoshida K, Nakatani T, Honda E, Hayakawa S, Furuyama K, Hayashi N. Role of the heme regulatory motif in the heme‐mediated inhibition of mitochondrial import of 5‐aminolevulinate synthase. J Biochem 136: 233‐238, 2004.
 170. Murzin AG, Brenner SE, Hubbard T, Chothia C. SCOP: A structural classification of proteins database for the investigation of sequences and structures. J Mol Biol 247: 536‐540, 1995.
 171. Mustajoki P, Nordmann Y. Early administration of heme arginate for acute porphyric attacks. Arch Intern Med 153: 2004‐2008, 1993.
 172. Naito Y, Takagi T, Yoshikawa T. Heme oxygenase‐1: A new therapeutic target for inflammatory bowel disease. Aliment Pharmacol Ther 20 (Suppl 1): 177‐184, 2004.
 173. Nguyen L, Blust M, Bailin M, Melendez L, Raines DE. Photosensitivity and perioperative polyneuropathy complicating orthotopic liver transplantation in a patient with erythropoietic protoporphyria. Anesthesiology 91: 1173‐1175, 1999.
 174. Nielsen B, Thorn NA. Transient excess urinary excretion of antidiuretic material in acute intermittent porphyria with hyponatremia and hypomagnesemia. Am J Med 38: 345‐358, 1965.
 175. Nonaka S, Nishimoto K, Hirowatari T, Honda T, Nogita M. Electron microscopic study of porphyrias. J Dermatol 2: 87‐92, 1975.
 176. O'Connor J, Tishler PV, Gordon B. Prevalence of intermittent acute porphyria in psychiatric and normal populations. Biochem Genet 16: 37A, 1978.
 177. O'Reilly FM, Darby C, Fogarty J, Tormey W, Kay EW, Leader M, Murphy GM. Screening of patients with iron overload to identify hemochromatosis and porphyria cutanea tarda. Arch Dermatol 133: 1098‐1101, 1997.
 178. Obornik M, Green BR. Mosaic origin of the heme biosynthesis pathway in photosynthetic eukaryotes. Mol Biol Evol 22: 2343‐2353, 2005.
 179. Ogawa K, Sun J, Taketani S, Nakajima O, Nishitani C, Sassa S, Hayashi N, Yamamoto M, Shibahara S, Fujita H, Igarashi K. Heme mediates derepression of Maf recognition element through direct binding to transcription repressor Bach1. EMBO J 20: 2835‐2843, 2001.
 180. Oyake T, Itoh K, Motohashi H, Hayashi N, Hoshino H, Nishizawa M, Yamamoto M, Igarashi K. Bach proteins belong to a novel family of BTB‐basic leucine zipper transcription factors that interact with MafK and regulate transcription through the NF‐E2 site. Mol Cell Biol 16: 6083‐6095, 1996.
 181. Paoli M, Marles‐Wright J, Smith A. Structure‐function relationships in heme‐proteins. DNA Cell Biol 21: 271‐280, 2002.
 182. Perlroth MG, Tschudy DP, Marver HS, Berard CW, Zeigel RF, Rechcigl M, Collins A. Acute intermittent porphyria. New morphologic and biochemical findings. Am J Med 41: 149‐162, 1966.
 183. Peyer AK, Jung D, Beer M, Gnerre C, Keogh A, Stroka D, Zavolan M, Meyer UA. Regulation of human liver delta‐aminolevulinic acid synthase by bile acids. Hepatology 46: 1960‐1970, 2007.
 184. Pierach CA. Hematin therapy for the porphyric attack. Semin Liver Dis 2: 125‐131, 1982.
 185. Pimstone NR. Hematologic and hepatic manifestations of the cutaneous porphyrias. Clin Dermatol 3: 83‐102, 1985.
 186. Pimstone NR, Gandhi SN, Mukerji SK. Therapeutic efficacy of oral charcoal in congenital erythropoietic porphyria. N Engl J Med 316: 390‐393, 1987.
 187. Podvinec M, Handschin C, Looser R, Meyer UA. Identification of the xenosensors regulating human 5‐aminolevulinate synthase. Proc Natl Acad Sci U S A 101: 9127‐9132, 2004.
 188. Poh‐Fitzpatrick MB. A plasma porphyrin fluorescence marker for variegate porphyria. Arch Dermatol 116: 543‐547, 1980.
 189. Poh‐Fitzpatrick MB. The erythropoietic porphyrias. Dermatol Clin 4: 291‐296, 1986.
 190. Poh‐Fitzpatrick MB, DeLeo VA. Rates of plasma porphyrin disappearance in fluorescent vs. red incandescent light exposure. J Invest Dermatol 69: 510‐512, 1977.
 191. Poh‐Fitzpatrick MB, Lamola AA. Comparative study of protoporphyrins in erythropoietic protoporphyria and griseofulvin‐induced murine protoporphyria. Binding affinities, distribution, and fluorescence spectra in various blood fractions. J Clin Invest 60: 380‐389, 1977.
 192. Popescu I, Dima SO. Domino liver transplantation: How far can we push the paradigm? Liver Transpl 18: 22‐28, 2012.
 193. Poss KD, Tonegawa S. Reduced stress defense in heme oxygenase 1‐deficient cells. Proc Natl Acad Sci U S A 94: 10925‐10930, 1997.
 194. Poulos TL. The Janus nature of heme. Nat Prod Rep 24: 504‐510, 2007.
 195. Pulkkinen KH, Yla‐Herttuala S, Levonen AL. Heme oxygenase 1 is induced by miR‐155 via reduced BACH1 translation in endothelial cells. Free Radic Biol Med 51: 2124‐2131.
 196. Puy H, Deybach JC, Baudry P, Callebert J, Touitou Y, Nordmann Y. Decreased nocturnal plasma melatonin levels in patients with recurrent acute intermittent porphyria attacks. Life Sci 53: 621‐627, 1993.
 197. Raghuram S, Stayrook KR, Huang P, Rogers PM, Nosie AK, McClure DB, Burris LL, Khorasanizadeh S, Burris TP, Rastinejad F. Identification of heme as the ligand for the orphan nuclear receptors REV‐ERBalpha and REV‐ERBbeta. Nat Struct Mol Biol 14: 1207‐1213, 2007.
 198. Rand EB, Bunin N, Cochran W, Ruchelli E, Olthoff KM, Bloomer JR. Sequential liver and bone marrow transplantation for treatment of erythropoietic protoporphyria. Pediatrics 118: e1896‐1899, 2006.
 199. Rank JM, Carithers R, Bloomer J. Evidence for neurological dysfunction in end‐stage protoporphyric liver disease. Hepatology 18: 1404‐1409, 1993.
 200. Reichheld JH, Katz E, Banner BF, Szymanski IO, Saltzman JR, Bonkovsky HL. The value of intravenous heme‐albumin and plasmapheresis in reducing postoperative complications of orthotopic liver transplantation for erythropoietic protoporphyria. Transplantation 67: 922‐928, 1999.
 201. Reisenauer AK, Soon SL, Lee KK, Hanifin JM. Erythropoietic protoporphyria presenting with liver failure in adulthood. Dermatology 210: 72‐73, 2005.
 202. Reuben A. Seeing purple. Hepatology 43: 1403‐1409, 2006.
 203. Rhie G, Beale SI. Regulation of heme oxygenase activity in Cyanidium caldarium by light, glucose, and phycobilin precursors. J Biol Chem 269: 9620‐9626, 1994.
 204. Roberts DT, Brodie MJ, Moore MR, Thompson GG, Goldberg A, MacSween RN. Hereditary coproporphyria presenting with photosensitivity induced by the contraceptive pill. Br J Dermatol 96: 549‐554, 1977.
 205. Rufenacht UB, Gouya L, Schneider‐Yin X, Puy H, Schafer BW, Aquaron R, Nordmann Y, Minder EI, Deybach JC. Systematic analysis of molecular defects in the ferrochelatase gene from patients with erythropoietic protoporphyria. Am J Hum Genet 62: 1341‐1352, 1998.
 206. Sarkany RP. Making sense of the porphyrias. Photodermatol Photoimmunol Photomed 24: 102‐108, 2008.
 207. Sarkany RP, Alexander GJ, Cox TM. Recessive inheritance of erythropoietic protoporphyria with liver failure. Lancet 343: 1394‐1396, 1994.
 208. Schmidt H, Snitker G, Thomsen K, Lintrup J. Erythropoietic protoporphyria. A clinical study based on 29 cases in 14 families. Arch Dermatol 110: 58‐64, 1974.
 209. Schneider S, Marles‐Wright J, Sharp KH, Paoli M. Diversity and conservation of interactions for binding heme in b‐type heme proteins. Nat Prod Rep 24: 621‐630, 2007.
 210. Schwartz S, Johnson JA, Stephenson BD, Anderson AS, Edmondson PR, Fusaro RM. Erythropoietic defects in protoporphyria: A study of factors involved in labelling of porphyrins and bile pigments from ALA‐ 3 H and glycine‐ 14 C. J Lab Clin Med 78: 411‐434, 1971.
 211. Schwartz S, O'Connor N, Stephenson BD, Anderson AS, Johnson LW, Johnson J. Turnover of erythrocyte protoporphyrin, with special reference to bovine porphyria and iron deficiency anemia. Ann Clin Res 8 (Suppl 17): 203‐212, 1976.
 212. Seth AK, Badminton MN, Mirza D, Russell S, Elias E. Liver transplantation for porphyria: Who, when, and how? Liver Transpl 13: 1219‐1227, 2007.
 213. Shan Y, Lambrecht RW, Donohue SE, Bonkovsky HL. Role of Bach1 and Nrf2 in up‐regulation of the heme oxygenase‐1 gene by cobalt protoporphyrin. FASEB J 20: 2651‐2653, 2006.
 214. Shan Y, Lambrecht RW, Ghaziani T, Donohue SE, Bonkovsky HL. Role of Bach‐1 in regulation of heme oxygenase‐1 in human liver cells: Insights from studies with small interfering RNAS. J Biol Chem 279: 51769‐51774, 2004.
 215. Shan Y, Pepe J, Lambrecht RW, Bonkovsky HL. Mapping of the chick heme oxygenase‐1 proximal promoter for responsiveness to metalloporphyrins. Arch Biochem Biophys 399: 159‐166, 2002.
 216. Shan Y, Pepe J, Lu TH, Elbirt KK, Lambrecht RW, Bonkovsky HL. Induction of the heme oxygenase‐1 gene by metalloporphyrins. Arch Biochem Biophys 380: 219‐227, 2000.
 217. Shan Y, Zheng J, Lambrecht RW, Bonkovsky HL. Reciprocal effects of micro‐RNA‐122 on expression of heme oxygenase‐1 and hepatitis C virus genes in human hepatocytes. Gastroenterology 133: 1166‐1174, 2007.
 218. Shehan JM, Huerter CJ. Porphyria cutanea tarda associated with an acute gastrointestinal bleed: The roles of supplemental iron and blood transfusion. Cutis 68: 147‐150, 2001.
 219. Shekhawat GS, Verma K. Haem oxygenase (HO): An overlooked enzyme of plant metabolism and defence. J Exp Bot 61: 2255‐2270.
 220. Sherman IW. Twelve Diseases that Changed Our World. Washington, DC: ASM Press, 2007.
 221. Soonawalla ZF, Orug T, Badminton MN, Elder GH, Rhodes JM, Bramhall SR, Elias E. Liver transplantation as a cure for acute intermittent porphyria. Lancet 363: 705‐706, 2004.
 222. Stein JA, Tschudy DP. Acute intermittent porphyria. A clinical and biochemical study of 46 patients. Medicine (Baltimore) 49: 1‐16, 1970.
 223. Stelter M, Melo AM, Pereira MM, Gomes CM, Hreggvidsson GO, Hjorleifsdottir S, Saraiva LM, Teixeira M, Archer M. A novel type of monoheme cytochrome c: Biochemical and structural characterization at 1.23 A resolution of rhodothermus marinus cytochrome c. Biochemistry (Mosc) 47: 11953‐11963, 2008.
 224. Sterling RK, Bralow S. Extrahepatic manifestations of hepatitis C virus. Curr Gastroenterol Rep 8: 53‐59, 2006.
 225. Stocker R, Yamamoto Y, McDonagh AF, Glazer AN, Ames BN. Bilirubin is an antioxidant of possible physiological importance. Science 235: 1043‐1046, 1987.
 226. Stokvis B. Concerning two unusual pigments in the urine of patients. Ned Tijdschr Geneeskd 25: 409, 1889.
 227. Straka JG, Hill HD, Krikava JM, Kools AM, Bloomer JR. Immunochemical studies of ferrochelatase protein: Characterization of the normal and mutant protein in bovine and human protoporphyria. Am J Hum Genet 48: 72‐78, 1991.
 228. Sun J, Hoshino H, Takaku K, Nakajima O, Muto A, Suzuki H, Tashiro S, Takahashi S, Shibahara S, Alam J, Taketo MM, Yamamoto M, Igarashi K. Hemoprotein Bach1 regulates enhancer availability of heme oxygenase‐1 gene. EMBO J 21: 5216‐5224, 2002.
 229. Surinya KH, Cox TC, May BK. Identification and characterization of a conserved erythroid‐specific enhancer located in intron 8 of the human 5‐aminolevulinate synthase 2 gene. J Biol Chem 273: 16798‐16809, 1998.
 230. Sweeney GD. Porphyria cutanea tarda, or the uroporphyrinogen decarboxylase deficiency diseases. Clin Biochem 19: 3‐15, 1986.
 231. Taketani S, Inazawa J, Nakahashi Y, Abe T, Tokunaga R. Structure of the human ferrochelatase gene. Exon/intron gene organization and location of the gene to chromosome 18. Eur J Biochem 205: 217‐222, 1992.
 232. Tanaka R, Tanaka A. Tetrapyrrole biosynthesis in higher plants. Annu Rev Plant Biol 58: 321‐346, 2007.
 233. Tanaka S, Akaike T, Fang J, Beppu T, Ogawa M, Tamura F, Miyamoto Y, Maeda H. Antiapoptotic effect of haem oxygenase‐1 induced by nitric oxide in experimental solid tumour. Br J Cancer 88: 902‐909, 2003.
 234. Tang XD, Xu R, Reynolds MF, Garcia ML, Heinemann SH, Hoshi T. Haem can bind to and inhibit mammalian calcium‐dependent Slo1 BK channels. Nature 425: 531‐535, 2003.
 235. Thunell S, Henrichson A, Floderus Y, Groth CG, Eriksson BG, Barkholt L, Nemeth A, Strandvik B, Eleborg L, Holmberg L. Liver transplantation in a boy with acute porphyria due to δ‐aminolaevulinate dehydratase deficiency. Eur J Clin Chem Clin Biochem 30: 599‐606, 1992.
 236. Tian Q, Li T, Hou W, Zheng J, Schrum LW, Bonkovsky HL. Lon peptidase 1 (LONP1)‐dependent breakdown of mitochondrial 5‐aminolevulinic acid synthase protein by heme in human liver cells. J Biol Chem 286: 26424‐26430, 2011.
 237. Tishler PV, Woodward B, O'Connor J, Holbrook DA, Seidman LJ, Hallett M, Knighton DJ. High prevalence of intermittent acute porphyria in a psychiatric patient population. AJ Psychiatry 142: 1430‐1436, 1985.
 238. Todd DJ. Gallstones in children. Am J Dis Child 145: 971‐972, 1991.
 239. Todd DJ, Callender ME, Mayne EE, Walsh M, Burrows D. Erythropoietic protoporphyria, transfusion therapy and liver disease. Br J Dermatol 127: 534‐537, 1992.
 240. Vreman HJ, Stevenson DK. Heme oxygenase activity as measured by carbon monoxide production. Anal Biochem 168: 31‐38, 1988.
 241. Wahlin S, Aschan J, Bjornstedt M, Broome U, Harper P. Curative bone marrow transplantation in erythropoietic protoporphyria after reversal of severe cholestasis. J Hepatol 46: 174‐179, 2007.
 242. Wahlin S, Harper P, Sardh E, Andersson C, Andersson DE, Ericzon BG. Combined liver and kidney transplantation in acute intermittent porphyria. Transpl Int 23: e18‐21, 2010.
 243. Wahlin S, Stal P, Adam R, Karam V, Porte R, Seehofer D, Gunson BK, Hillingso J, Klempnauer JL, Schmidt J, Alexander G, O'Grady J, Clavien PA, Salizzoni M, Paul A, Rolles K, Ericzon BG, Harper P. Liver transplantation for erythropoietic protoporphyria in Europe. Liver Transpl 17: 1021‐1026, 2011.
 244. Waldenstrom J. Studien ueber Porphyrie. Acta Med Scand 82 (Suppl): 1‐254, 1937.
 245. Waldenstrom J. The porphyrias as inborn errors of metabolism. Am J Med 22: 758‐773, 1957.
 246. WaldenstrÖM JAN. Some observations on acute porphyria and other conditions with a change in the excretion of porphyrins. Acta Med Scand 83: 281‐316, 1934.
 247. Whatley SD, Ducamp S, Gouya L, Grandchamp B, Beaumont C, Badminton MN, Elder GH, Holme SA, Anstey AV, Parker M, Corrigall AV, Meissner PN, Hift RJ, Marsden JT, Ma Y, Mieli‐Vergani G, Deybach JC, Puy H. C‐terminal deletions in the ALAS2 gene lead to gain of function and cause X‐linked dominant protoporphyria without anemia or iron overload. Am J Hum Genet 83: 408‐414, 2008.
 248. Whitcombe DM, Carter NP, Albertson DG, Smith SJ, Rhodes DA, Cox TM. Assignment of the human ferrochelatase gene (FECH) and a locus for protoporphyria to chromosome 18q22. Genomics 11: 1152‐1154, 1991.
 249. Windebank AJ, Bonkovsky HL. Porphyric Neuropathy. In: Dyck PJ, Thomas PK, Griffin JW, Low PA, Poduslo JF, editors. Peripheral Neuropathy (3rd ed). Philadelphia: Saunders, 1993, pp. 1161‐1168.
 250. Winkler MG, Anderson KE. Vampires, porphyria, and the media: Medicalization of a myth. Perspect Biol Med 33: 598‐611, 1990.
 251. Wu N, Yin L, Hanniman EA, Joshi S, Lazar MA. Negative feedback maintenance of heme homeostasis by its receptor, Rev‐erbalpha. Genes Dev 23: 2201‐2209, 2009.
 252. Yachie A, Niida Y, Wada T, Igarashi N, Kaneda H, Toma T, Ohta K, Kasahara Y, Koizumi S. Oxidative stress causes enhanced endothelial cell injury in human heme oxygenase‐1 deficiency. J Clin Invest 103: 129‐135, 1999.
 253. Yamada N, Yamaya M, Okinaga S, Nakayama K, Sekizawa K, Shibahara S, Sasaki H. Microsatellite polymorphism in the heme oxygenase‐1 gene promoter is associated with susceptibility to emphysema. Am J Hum Genet 66: 187‐195, 2000.
 254. Yamaguchi T, Komoda Y, Nakajima H. Biliverdin‐IX alpha reductase and biliverdin‐IX beta reductase from human liver. Purification and characterization. J Biol Chem 269: 24343‐24348, 1994.
 255. Yamamoto M, Hayashi N, Kikuchi G. Evidence for the transcriptional inhibition by heme of the synthesis of delta‐aminolevulinate synthase in rat liver. Biochem Biophys Res Commun 105: 985‐990, 1982.
 256. Yamamoto M, Kure S, Engel JD, Hiraga K. Structure, turnover, and heme‐mediated suppression of the level of mRNA encoding rat liver delta‐aminolevulinate synthase. J Biol Chem 263: 15973‐15979, 1988.
 257. Yeung Laiwah AC, Moore MR, Goldberg A. Pathogenesis of acute porphyria. Q J Med 63: 377‐392, 1987.
 258. Yin L, Wu N, Curtin JC, Qatanani M, Szwergold NR, Reid RA, Waitt GM, Parks DJ, Pearce KH, Wisely GB, Lazar MA. Rev‐erbalpha, a heme sensor that coordinates metabolic and circadian pathways. Science 318: 1786‐1789, 2007.
 259. Zenke‐Kawasaki Y, Dohi Y, Katoh Y, Ikura T, Ikura M, Asahara T, Tokunaga F, Iwai K, Igarashi K. Heme induces ubiquitination and degradation of the transcription factor Bach1. Mol Cell Biol 27: 6962‐6971, 2007.
 260. Zhang FL, Shen GM, Liu XL, Wang F, Zhao HL, Yu J, Zhang JW. Hypoxic induction of human erythroid‐specific delta‐aminolevulinate synthase mediated by hypoxia‐inducible factor 1. Biochemistry (Mosc) 50: 1194‐1202, 2011.
 261. Zhang YK, Yeager RL, Klaassen CD. Circadian expression profiles of drug‐processing genes and transcription factors in mouse liver. Drug Metab Dispos 37: 106‐115, 2009.
 262. Zheng J, Tian Q, Hou W, Watts JA, Schrum LW, Bonkovsky HL. Tissue‐specific expression of ALA synthase‐1 and heme oxygenase‐1 and their expression in livers of rats chronically exposed to ethanol. FEBS Lett 582: 1829‐1834, 2008.
 263. Zhu Z, Wilson AT, Mathahs MM, Wen F, Brown KE, Luxon BA, Schmidt WN. Heme oxygenase‐1 suppresses hepatitis C virus replication and increases resistance of hepatocytes to oxidant injury. Hepatology 48: 1430‐1439, 2008.

Contact Editor

Submit a note to the editor about this article by filling in the form below.

* Required Field

Article Title: Porphyrin and Heme Metabolism and the Porphyrias
 

How to Cite

Herbert L. Bonkovsky, Jun‐Tao Guo, Weihong Hou, Ting Li, Tarun Narang, Manish Thapar. Porphyrin and Heme Metabolism and the Porphyrias. Compr Physiol 2013, 3: 365-401. doi: 10.1002/cphy.c120006