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

Author:

SINCLAIR R. Peter12,GORMAN Nadia12,DALTON Tim3,WALTON S. Heidi12,BEMENT J. William1,SINCLAIR F. Jacqueline12,SMITH G. Andrew4,NEBERT W. Daniel3

Affiliation:

1. VA Medical Center, White River Junction, VT 05009, U.S.A.

2. Departments of Biochemistry and Pharmacology/Toxicology, Dartmouth Medical School, Hanover, NH 03755, U.S.A.

3. Department of Environmental Health and Center for Environmental Genetics, University of Cincinnati Medical Center, P.O. Box 670056, Cincinnati, OH 45267-0056, U.S.A.

4. MRC Toxicology Unit, University of Leicester, Leicester LE1 9HN, U.K.

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.

Publisher

Portland Press Ltd.

Subject

Cell Biology,Molecular Biology,Biochemistry

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