Abstract
Accumulating evidence, including experiments using cytochrome P450 1a2 (Cyp1a2) gene knock-out mice (Cyp1a2(−/−)), indicates that the development of chemically induced porphyria requires the expression of CYP1A2. It has also been demonstrated that iron enhances and expedites the development of experimental uroporphyria, but that iron alone without CYP1A2 expression, as in Cyp1a2(−/−) mice, does not cause uroporphyria. The role of iron in the development of porphyria has not been elucidated. We examined the in vivo effect of iron deficiency on hepatic URO accumulation in experimental porphyria. Mice were fed diets containing low (iron-deficient diet (IDD), 8.5 mg iron/kg) or normal (normal diet (ND), 213.7 mg iron/kg) levels of iron. They were treated with 3-methylcholanthrene (MC), an archetypal inducer of CYP1A, and 5-aminolevulinate (ALA), precursors of porphyrin and heme. We found that uroporphyrin (URO) levels and uroporphyrinogen oxidation (UROX) activity were markedly increased in ND mice treated with MC and ALA, while the levels were not raised in IDD mice with the same treatments. CYP1A2 levels and methoxyresorufin O-demethylase (MROD) activities, the CYP1A2-mediated reaction, were markedly induced in the livers of both ND and IDD mice treated with MC and ALA. UROX activity, supposedly a CYP1A2-dependent activity, was not enhanced in iron-deficient mice in spite of the fact of induction of CYP1A2. We showed that a sufficient level of iron is essential for the development of porphyria and UROX activity.
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References
Becker FT (1965) Porphyria cutanea tarda induced by estrogens. Arch Dermatol 92:252–255. doi:10.1001/archderm.92.3.252
Bonkovsky HL, Wood SG, Howell SK, Sinclair PR, Lincoln B, Healey JF, Sinclair JF (1986) High-performance liquid chromatographic separation and quantitation of tetrapyrroles from biological materials. Anal Biochem 155:56–64. doi:10.1016/0003-2697(86)90224-1
Burke MD, Thompson S, Elcombe CR, Halpert J, Haaparanta T, Mayer RT (1985) Ethoxy-, pentoxy- and benzyloxyphenoxazones and homologues: a series of substrates to distinguish between different induced cytochromes P-450. Biochem Pharmacol 34:3337–3345. doi:10.1016/0006-2952(85)90355-7
Chaufan G, Rios de Molina MC, de Viale LCSM (2001) How does hexachlorobenzene treatment affect liver uroporphyrinogen decarboxylase? Int J Biochem Cell Biol 33:621–630. doi:10.1016/S1357-2725(01)00034-6
Clark MA, Bing BA, Gottschall PE, Williams JF (1995) Differential effect of cytokines on the phenobarbital or 3-methylcholanthrene induction of P450 mediated monooxygenase activity in cultured rat hepatocytes. Biochem Pharmacol 49:97–104. doi:10.1016/0006-2952(94)00438-R
Deam S, Elder GH (1991) Uroporphyria produced in mice by iron and 5-aminolevulinic acid. Biochem Pharmacol 41(12):2019–2022
Enriquez de Salamanca R, Mingo D, Chinarro S, Munoz JJ, Perpina J (1982) Patterns of porphyrin-excretion in female estrogen-induced porphyria cutanea tarda. Arch Dermatol Res 274:179–184. doi:10.1007/BF00510371
Epstein JH, Redeker AG (1965) Porphyria cutanea tarda symptomatica (PCT-S). A study of the effect of phlebotomy therapy. Arch Dermatol 92:286–289. doi:10.1001/archderm.92.3.286
Francis JE, Smith AG (1984) Assay of mouse liver uroporphyrinogen decarboxylase by reverse-phase high-performance liquid chromatography. Anal Biochem 138:404–410. doi:10.1016/0003-2697(84)90829-7
Gorman N, Walton HS, Bement WJ, Honsinger CP, Szakacs JG, Sinclair JF, Sinclair PR (1999) Role of small differences in CYP1A2 in the development of uroporphyria produced by iron and 5-aminolevulinate in C57BL/6 and SWR strains of mice. Biochem Pharmacol 58:375–382. doi:10.1016/S0006-2952(99)00088-X
Gorman N, Ross KL, Walton HS, Bement WJ, Szakacs JG, Gerhard GS, Dalton TP, Nebert DW, Eisenstein RS, Sinclair JF, Sinclair PR (2002) Uroporphyria in mice: thresholds for hepatic CYP1A2 and iron. Hepatology 35:912–921. doi:10.1053/jhep.2002.32487
Jarrell JF, Gocmen A, Akyol D, Brant R (2002) Hexachlorobenzene exposure and the proportion of male births in Turkey 1935–1990. Reprod Toxicol 16:65–70. doi:10.1016/S0890-6238(01)00196-4
Jones KG, Sweeney GD (1977) Association between induction of aryl hydrocarbon hydroxylase and depression of uroporphyrinogen decarboxylase activity. Res Commun Chem Pathol Pharmacol 17:631–637
Lambrecht RW, Jacobs JM, Sinclair PR, Sinclair JF (1990) Inhibition of uroporphyrinogen decarboxylase activity. The role of cytochrome P-450-mediated uroporphyrinogen oxidation. Biochem J 269:437–441
Lambrecht RW, Sinclair PR, Gorman N, Sinclair JF (1992) Uroporphyrinogen oxidation catalyzed by reconstituted cytochrome P450IA2. Arch Biochem Biophys 294:504–510. doi:10.1016/0003-9861(92)90717-B
Lowry OH, Rosebrough HJ, Farr AL, Randall RJ (1951) Protein measurement with the Folin phenol reagent. J Biol Chem 193:265–275
Nonaka S, Ohgami T, Murayama F, Yamashita K, Yoshida H (1986) Five cases of porphyria cutanea tarda with mild cutaneous changes: evaluation of the efficacy of phlebotomy by the pattern analysis of urinary porphyrins. J Dermatol 13:196–202
Omura T, Sato R (1964) The carbon monooxide-binding pigment of liver microsomes. J Biol Chem 239:370–2378
Phillips JD, Jackson LK, Bunting M, Franklin MR, Thomas KR, Levy JE, Andrews NC, Kushner JP (2001) A mouse model of familial porphyria cutanea tarda. Proc Natl Acad Sci USA 98:259–264. doi:10.1073/pnas.011481398
Schoenfeld N, Mamet R, Leibovici L, Lanir A (1996) Alcohol-induced changes in urinary aminolevulinic acid and porphyrins: unrelated to liver disease. Alcohol 13:59–63. doi:10.1016/0741-8329(95)02013-6
Sinclair PR, Gorman N, Dalton T, Walton HS, Bement WJ, Sinclair JF, Smith AG, Nebert DW (1998) Uroporphyria produced in mice by iron and 5-aminolevulinic acid does not occur in Cyp1a2(−/−) null mutant mice. Biochem J 330:149–153
Sinclair PR, Gorman N, Sinclair JF, Walton HS, Bement WJ, Lambrecht RW (1995) Ascorbic acid inhibits chemically induced uroporphyria in ascorbate-requiring rats. Hepatology 22:565–572
Smith AG, Francis JE (1983) Synergism of iron and hexachlorobenzene inhibits hepatic uroporphyrinogen decarboxylase in inbred mice. Biochem J 214:909–913
Smith AG, Francis JE (1993) Genetic variation of iron-induced uroporphyria in mice. Biochem J 291:29–35
Smith AG, Cabral JR, Carthew P, Francis JE, Manson MM (1989) Carcinogenicity of iron in conjunction with a chlorinated environmental chemical, hexachlorobenzene, in C57BL/10ScSn mice. Int J Cancer 43:492–496. doi:10.1002/ijc.2910430325
Smith AG, Clothier B, Carthew P, Childs NL, Sinclair PR, Nebert DW, Dalton TP (2001) Protection of the Cyp1a2(−/−) null mouse against uroporphyria and hepatic injury following exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin. Toxicol Appl Pharmacol 173:89–98. doi:10.1006/taap.2001.9167
Smith AG, Clothier B, Robinson S, Scullion MJ, Carthew P, Edwards R, Luo J, Lim CK, Toledano M (1998) Interaction between iron metabolism and 2,3,7,8-tetrachlorodibenzo-p-dioxin in mice with variants of the Ahr gene: a hepatic oxidative mechanism. Mol Pharmacol 53:52–61
Smith AG, Francis JE (1987) Chemically-induced formation of an inhibitor of hepatic uroporphyrinogen decarboxylase in inbred mice with iron overload. Biochem J 246:221–226
Smith AG, Francis JE, Green JA, Greig JB, Wolf CR, Manson MM (1990) Sex-linked hepatic uroporphyria and the induction of cytochromes P450IA in rats caused by hexachlorobenzene and polyhalogenated biphenyls. Biochem Pharmacol 40:2059–2068. doi:10.1016/0006-2952(90)90236-E
Sweeney GD, Jones KG, Cole FM, Basford D, Krestynski F (1979) Iron deficiency prevents liver toxicity of 2,3,7,8-tetrachlorodibenzo-p-dioxin. Science 204:332–335. doi:10.1126/science.432648
Towbin H, Staehelin T, Gordon J (1979) Electrophoretic transfer of proteins from polyacrylamide gels to nitrocellulose sheets: procedure and some applications. Proc Natl Acad Sci USA 76:4350–4354. doi:10.1073/pnas.76.9.4350
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Nakano, K., Ishizuka, M., Sakamoto, K.Q. et al. Absolute requirement for iron in the development of chemically induced uroporphyria in mice treated with 3-methylcholanthrene and 5-aminolevulinate. Biometals 22, 345–351 (2009). https://doi.org/10.1007/s10534-008-9171-6
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DOI: https://doi.org/10.1007/s10534-008-9171-6