title: CYP1A2 is essential in murine uroporphyria caused by hexachlorobenzene and iron.
abstract: Using Cyp1a2(-/-) mice we previously showed that CYP1A2 is absolutely required for hepatic uroporphyrin accumulation caused by iron and 5-aminolevulinate (ALA) treatment, both in the presence and absence of an inducer of CYP1A2. In this study we have used these mice to investigate whether CYP1A2 has an obligatory role in hepatic uroporphyria caused by hexachlorobenzene (HCBZ), an inducer of CYP2B and CYP3A, as well as CYP1A2. Here we treated mice with HCBZ and iron, with and without the porphyrin precursor, ALA, in the drinking water. In iron-loaded wild-type mice given a single dose of HCBZ and ALA, hepatic uroporphyrin (URO) accumulated to 300 nmol/g liver after 37 days, whereas in Cyp1a2(-/-) mice, there was no hepatic URO, even after an additional dose of HCBZ, and a further 29 days of ALA treatment. A similar requirement for CYP1A2 was found in uroporphyria produced in HCBZ and iron-treated mice in the absence of ALA. As detected by Western immunoblotting, HCBZ induced small increases in CYP2B and CYP3A in the livers of all animals. In the wild-type animals, HCBZ also induced CYP1A2 and associated enzyme activities, including uroporphyrinogen oxidation, by about 2-3-fold. In the Cyp1a2(-/-) mice, HCBZ did not increase hepatic microsomal uroporphyrinogen oxidation. These results indicate that, in mice, CYP1A2 is essential in the process leading to HCBZ-induced uroporphyria. Contributions by other CYP forms induced by HCBZ appear to be minimal.
authors.affiliation: VA Medical Center, White River Junction, Vermont, 05009, USA.
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: T P
authors.initials: TP
authors.lastname: Dalton
authors.forename: J F
authors.initials: JF
authors.lastname: Sinclair
authors.forename: A G
authors.initials: AG
authors.lastname: Smith
authors.forename: D W
authors.initials: DW
authors.lastname: Nebert
mesh_terms: D000622:Aminolevulinic Acid / Q000494:pharmacology; D000818:Animals; D000906:Antibodies / Q000276:immunology; D015153:Blotting, Western; D056486:Chemical and Drug Induced Liver Injury; D019388:Cytochrome P-450 CYP1A2 / Q000378:metabolism / Q000502:physiology*; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004347:Drug Interactions; D004790:Enzyme Induction / Q000187:drug effects*; D007093:Imidazoles / Q000633:toxicity*; D007501:Iron / Q000633:toxicity*; D008099:Liver / Q000737:chemistry; D008297:Male; D008748:Methylcholanthrene / Q000633:toxicity; D051379:Mice; D008810:Mice, Inbred C57BL; D008862:Microsomes, Liver / Q000378:metabolism*; D010078:Oxazines / Q000378:metabolism; D010084:Oxidation-Reduction; D010634:Phenobarbital / Q000633:toxicity; D013997:Time Factors; D014577:Uroporphyrinogens / Q000378:metabolism; D014578:Uroporphyrins / Q000378:metabolism*
chemical_list: D000906:Antibodies; D007093:Imidazoles; D010078:Oxazines; D014577:Uroporphyrinogens; D014578:Uroporphyrins; C049400:4-hydroxycibenzoline; D008748:Methylcholanthrene; C007649:ethoxyresorufin; D000622:Aminolevulinic Acid; D003577:Cytochrome P-450 Enzyme System; D007501:Iron; D019388:Cytochrome P-450 CYP1A2; D010634:Phenobarbital