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Publication Detail

Title: Uroporphyria produced in mice by iron and 5-aminolaevulinic acid does not occur in Cyp1a2(-/-) null mutant mice.

Authors: Sinclair, P R; Gorman, N; Dalton, T; Walton, H S; Bement, W J; Sinclair, J F; Smith, A G; Nebert, D W

Published In Biochem J, (1998 Feb 15)

Abstract: In the present study we have investigated the putative requirement for the cytochrome P-450 isoform CYP1A2 in murine uroporphyria, by comparing Cyp1a2(-/-) knockout mice with Cyp1a2(+/+) wild-type mice. Uroporphyria was produced by injecting animals with iron-dextran and giving the porphyrin precursor 5-aminolaevulinic acid in the drinking water. Some animals also received 3-methylcholanthrene (MC) to induce hepatic CYP1A2. In both protocols, uroporphyria was elicited by these treatments in the Cyp1a2(+/+) wild-type mice, but not in the null mutant mice. Uroporphyrinogen oxidation activity in hepatic microsomes from untreated Cyp1a2(+/+) mice was 2.5-fold higher than in Cyp1a2(-/-) mice. Treatment with MC increased hepatic CYP1A1 in both mouse lines and hepatic CYP1A2 only in the Cyp1a2(+/+) line, as determined by Western immunoblotting. MC increased hepatic ethoxy- and methoxy-resorufin O-dealkylase activities in both mouse lines, but increased uroporphyrinogen oxidation activity in the Cyp1a2(+/+) wild-type mice only. These results indicate the absolute requirement for hepatic CYP1A2 in causing experimental uroporphyria under the conditions used.

PubMed ID: 9461503 Exiting the NIEHS site

MeSH Terms: Aminolevulinic Acid/pharmacology*; Animals; Cytochrome P-450 CYP1A1/metabolism; Cytochrome P-450 CYP1A2/metabolism; Cytochrome P-450 CYP1A2/physiology*; Cytochrome P-450 Enzyme System/metabolism; Humans; Iron/pharmacology*; Liver/metabolism; Methylcholanthrene/pharmacology; Mice; Mice, Knockout; Microsomes, Liver/metabolism; Oxidoreductases/metabolism; Porphyrias/chemically induced*; Uroporphyrinogens/metabolism; Uroporphyrins/urine*

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