Absolute requirement for iron in the development of chemically induced uroporphyria in mice treated with 3-methylcholanthrene and 5-aminolevulinate |
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Authors: | Kenzi Nakano Mayumi Ishizuka Kentaro Q Sakamoto Shoichi Fujita |
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Institution: | (1) Laboratory of Toxicology, Department of Environmental Veterinary Sciences, Graduate School of Veterinary Medicine, Hokkaido University, N18 W9, Kita-ku, Sapporo 060-0818, Japan |
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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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Keywords: | Porphyria Uroporphyrin CYP1A2 Uroporphyrinogen oxidation Iron |
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