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. 1975 Sep;56(3):661–667. doi: 10.1172/JCI108136

The role of iron in the pathogenesis of porphyria cutanea tarda. II. Inhibition of uroporphyrinogen decarboxylase.

J P Kushner, D P Steinmuller, G R Lee
PMCID: PMC301914  PMID: 1159079

Abstract

Porphria cutanea tarda is characterized biochemically by excessive hepatic synthesis and urinary excretion of uroporphyrin I and 7-carboxylporphyrins. This pattern of excretion suggest an impaired ability to decarboxylate uroporphyrinogen to the paired ability to decarboxylate uroporphyringen to the 4-carboxyl porphyrinogen, coproporphyrinogen, a reaction catalyzed by the enzyme uroporphyringen decarboxylase. Because clinical evidence has implicated iron in the pathogenesis of porphyria cutanea tarda, these experiments were designed to study the effect of iron on uroporphyrinogen decarboxylase in procine crude liver extracts. Mitochondria-free crude liver extracts were preincubated with ferrous ion and aliquots were assayed for uroporphyrinogen decarboxylase activity. Uroporphyrinogens I and III, the substrates for the decarboxylase assay, were prepared enzymatically from (3H)porphobilinogen. The products of the decarboxylase reaction were identified and quantitated by three methods: (a) extraction into 1.5 N HCl and spectrophotometric quantitation; (b) adsorption onto talc, esterification, paper chromatographic identification, and quantitation by liquid scintillation counting; and (c) adsorption onto talc, esterification, thin-layer chromatographic identification on silica gel, and quantitation by liquid scintillation counting. The thin-layer scinllation method proved most sensitive as it was the only method which accurately identified and quantitated the 7-carboxyl porphyrin reaction product. Uroporphyrinogens I and III were decarboxylated at the same rate by porcine hepatic uroporphyrinogen decarboxylase, and the addition of iron induced marked inhibition of the decarboxylase activity. Ortholpehanthroline blocked the inhibitory effect of iron. The inhibition of uroporphyrinogen decarboxylase by ferrous ion, coupled with its previously reported inhibitory effect on uroporphyrinogen III cosynthetase, provides a possible biochemical explanation for the pattern of urinary porphyrin excretion observed in patients with porphyria cutanea tarda and the clinical association with disordered iron metabolism.

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Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. CORNFORD P. A., BENSON A. A qualitative and quantitative study of the separation of uroporphyrin octamethyl esters I and III by dioxan chromatography. J Chromatogr. 1963 Feb;10:141–157. doi: 10.1016/s0021-9673(01)92287-3. [DOI] [PubMed] [Google Scholar]
  2. Cornford P. Transformation of porphobilinogen into porphyrins by preparations from human erythrocytes. Biochem J. 1964 Apr;91(1):64–73. doi: 10.1042/bj0910064. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. DEAN G. THE PREVALENCE OF THE PORPHYRIAS. S Afr J Lab Clin Med. 1963 Dec;14:145–151. [PubMed] [Google Scholar]
  4. Dehlin O., Enerbäck L., Lundvall O. Porphyria cutanea tarda-a genetic disease? A biochemical and fluorescence microscopical study in four families. Acta Med Scand. 1973 Oct;194(4):265–270. [PubMed] [Google Scholar]
  5. Doss M. Analytical and preparative thin-layer chromatography of porphyrin methyl esters. Z Klin Chem Klin Biochem. 1970 May;8(3):197–207. doi: 10.1515/cclm.1970.8.3.197. [DOI] [PubMed] [Google Scholar]
  6. Doss M., Meinhof W., Look D., Henning H., Nawrocki P., Dölle W., Strohmeyer G., Filippini L. Porphyrins in liver and urine in acute intermittent and chronic hepatic porphyrias. S Afr Med J. 1971 Sep 25;:50–56. [PubMed] [Google Scholar]
  7. Dowdle E., Goldswain P., Spong N., Eales L. The pattern of porphyrin isomer accumulation and excretion in symptomatic porphyria. Clin Sci. 1970 Aug;39(2):147–158. doi: 10.1042/cs0390147. [DOI] [PubMed] [Google Scholar]
  8. Kushner J. P., Lee G. R., Nacht S. The role of iron in the pathogenesis of porphyria cutanea tarda. An in vitro model. J Clin Invest. 1972 Dec;51(12):3044–3051. doi: 10.1172/JCI107131. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. LAMONT N. M., HATHORN M., JOUBERT S. M. Porphyria in the African: a study of 100 cases. Q J Med. 1961 Oct;30:373–392. [PubMed] [Google Scholar]
  10. LOWRY O. H., ROSEBROUGH N. J., FARR A. L., RANDALL R. J. Protein measurement with the Folin phenol reagent. J Biol Chem. 1951 Nov;193(1):265–275. [PubMed] [Google Scholar]
  11. Levin E. Y. Enzymatic properties of uroporphyrinogen 3 cosynthetase. Biochemistry. 1971 Dec 7;10(25):4669–4675. doi: 10.1021/bi00801a012. [DOI] [PubMed] [Google Scholar]
  12. Lundvall O., Weinfeld A., Lundin P. Iron storage in porphyria cutanea tarda. Acta Med Scand. 1970 Jul-Aug;1-2(1):37–53. doi: 10.1111/j.0954-6820.1970.tb08003.x. [DOI] [PubMed] [Google Scholar]
  13. MAUZERALL D., GRANICK S. Porphyrin biosynthesis in erythrocytes. III. Uroporphyrinogen and its decarboxylase. J Biol Chem. 1958 Jun;232(2):1141–1162. [PubMed] [Google Scholar]
  14. Nacht S., San Martín de Viale L. C., Grinstein M. Human porphyria cutanea tarda. Isolation and properties of the urinary porphyrins. Clin Chim Acta. 1970 Mar;27(3):445–452. doi: 10.1016/0009-8981(70)90297-4. [DOI] [PubMed] [Google Scholar]
  15. Romeo G., Levin E. Y. Uroporphyrinogen decarboxylase from mouse spleen. Biochim Biophys Acta. 1971 Feb 23;230(2):330–341. doi: 10.1016/0304-4165(71)90220-0. [DOI] [PubMed] [Google Scholar]
  16. San Martin de Viale L. C., Viale A. A., Nacht S., Grinstein M. Experimental porphyria induced in rats by hexachlorobenzene. A study of the porphyrins excreted by urine. Clin Chim Acta. 1970 Apr;28(1):13–23. doi: 10.1016/0009-8981(70)90155-5. [DOI] [PubMed] [Google Scholar]
  17. Sancovich H. A., Battle A. M., Grinstein M. Porphyrin biosynthesis. VI. Separation and purification of porphobilinogen deaminase and uroporphyrinogen isomerase from cow liver. Porphobilinogenase an allosteric enzyme. Biochim Biophys Acta. 1969 Sep 30;191(1):130–143. doi: 10.1016/0005-2744(69)90322-2. [DOI] [PubMed] [Google Scholar]
  18. Shanley B. C., Zail S. S., Joubert S. M. Porphyrin metabolism in experimental hepatic siderosis in the rat. Br J Haematol. 1970 Jan;18(1):79–87. doi: 10.1111/j.1365-2141.1970.tb01420.x. [DOI] [PubMed] [Google Scholar]
  19. Taljaard J. J., Shanley B. C., Deppe W. M., Joubert S. M. Porphyrin metabolism in experimental hepatic siderosis in the rat. 3. Effect of iron overload and hexachlorobenzene on liver haem biosynthesis. Br J Haematol. 1972 Nov;23(5):587–593. doi: 10.1111/j.1365-2141.1972.tb07093.x. [DOI] [PubMed] [Google Scholar]
  20. Turnbull A., Baker H., Vernon-Roberts B., Magnus I. A. Iron metabolism in porphyria cutanea tarda and in erythropoietic protoporphyria. Q J Med. 1973 Apr;42(166):341–355. [PubMed] [Google Scholar]
  21. UYS C. J., EALES L. THE HISTOPATHOLOGY OF THE LIVER IN ACQUIRED (SYMPTOMATIC) PORPHYRIA. S Afr J Lab Clin Med. 1963 Dec;14:190–197. [PubMed] [Google Scholar]

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