UROPORPHYRIA PRODUCED IN MICE BY IRON AND 5-AMINOLEVULINIC ACID DOES NOT OCCUR IN CYP1A2(- -) NULL MUTANT MICE/

In the present study we have investigated the putative requirement for the cytochrome P-450 isoform CYP1A2 in murine uroporphyria, by compar ing Cypla2(-/-) knockout mice with Cypla2(+/+) wild-type mice, Uroporp hyria was produced by injecting animals with iron-dextran and giving t he porphyrin precursor 5-aminolaevulinic acid in the drinking water. S ome animals also received 3-methylcholanthrene (MC) to induce hepatic CYP1A2, In both protocols, uroporphyria was elicited by these treatmen ts in the Cypla2(+/+) wild-type mice, but not in the null mutant mice. Uroporphyrinogen oxidation activity in hepatic microsomes from untrea ted Cypla2(+/+) mice was 2.5-fold higher than in Cypla2(-/-) mice. Tre atment with MC increased hepatic CYP1A1 in both mouse lines and hepati c CYP1A2 only in the Cypla2(+/+) line, as determined by Western immuno blotting, MC increased hepatic ethoxy-and methoxy-resorufin O-dealkyla se activities in both mouse lines, but increased uroporphyrinogen oxid ation activity in the Cupla(+/+) wild-type mice only. These results in dicate the absolute requirement for hepatic CYP1A2 in causing experime ntal uroporphyria under the conditions used.