title: Relative roles of CYP2E1 and CYP1A2 in mouse uroporphyria caused by acetone.
abstract: Porphyria cutanea tarda is a liver disease characterized by excess production of uroporphyrin. We previously reported that acetone, an inducer of CYP2E1, enhances hepatic uroporphyrin accumulation in mice treated with iron dextran (Fe) and 5-aminolevulinic acid (ALA). Cyp2e1(-/-) mice treated with Fe and ALA were used to investigate whether CYP2E1 is required for the acetone effect. Hepatic uroporphyrin accumulation was stimulated by acetone in Cyp2e1(-/-) mice to the same extent as in wild-type mice. In the absence of acetone, uroporphyrin accumulated in Cyp2e1(-/-) mice treated with Fe and ALA, but less than in wildtype mice. However, in Cypla2(-/-) mice, uroporphyrin accumulation caused by Fe and ALA, with or without acetone, was completely prevented. Acetone was not an inducer of hepatic CYP1A2 in the wild-type mice. Although acetone is an inducer of CYP2E1, CYP1A2 appears to have the essential role in acetone-enhancement of uroporphyria.
authors.affiliation: VA Medical Center, White River Junction, Vermont 05009, USA. psinc@dartmouth.edu
authors.forename: P R
authors.initials: PR
authors.lastname: Sinclair
authors.forename: N
authors.initials: N
authors.lastname: Gorman
authors.forename: H S
authors.initials: HS
authors.lastname: Walton
authors.forename: W J
authors.initials: WJ
authors.lastname: Bement
authors.forename: J
authors.initials: J
authors.lastname: Szakacs
authors.forename: F J
authors.initials: FJ
authors.lastname: Gonzalez
authors.forename: T P
authors.initials: TP
authors.lastname: Dalton
authors.forename: D W
authors.initials: DW
authors.lastname: Nebert
authors.forename: J F
authors.initials: JF
authors.lastname: Sinclair
mesh_terms: D000096:Acetone / Q000494:pharmacology*; D000622:Aminolevulinic Acid / Q000494:pharmacology; D000818:Animals; D019388:Cytochrome P-450 CYP1A2 / Q000235:genetics / Q000502:physiology*; D019392:Cytochrome P-450 CYP2E1 / Q000235:genetics / Q000502:physiology*; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D007501:Iron / Q000378:metabolism / Q000494:pharmacology; D008099:Liver / Q000187:drug effects / Q000201:enzymology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology; D010088:Oxidoreductases / Q000378:metabolism; D017119:Porphyria Cutanea Tarda / Q000201:enzymology; D014577:Uroporphyrinogens / Q000378:metabolism; D014578:Uroporphyrins / Q000096:biosynthesis*
chemical_list: D014577:Uroporphyrinogens; D014578:Uroporphyrins; D000096:Acetone; D000622:Aminolevulinic Acid; D003577:Cytochrome P-450 Enzyme System; D007501:Iron; D010088:Oxidoreductases; C076307:methoxyresorufin-O-demethylase; D019392:Cytochrome P-450 CYP2E1; D019388:Cytochrome P-450 CYP1A2