title: Uroporphyrin accumulation in hepatoma cells expressing human or mouse CYP1A2: relation to the role of CYP1A2 in human porphyria cutanea tarda.
abstract: In experimental animals, CYP1A2 is absolutely required for the development of uroporphyria induced by treatment with polyhalogenated aromatic compounds or other compounds. Although the role of this CYP in clinical uroporphyria, porphyria cutanea tarda (PCT), is not clear, Cyp1a2(-/-) mice are resistant to the development of uroporphyria. Here, we compared the abilities of human and mouse CYP1A2 expressed in mouse hepatoma Hepa-1 cells to: (i) catalyze CYP1A2-dependent methoxyresorufin demethylase (MROD), and (ii) support uroporphyrin (URO) accumulation. Both CYP1A2 orthologs were expressed at similar levels as indicated by immunodetectable CYP1A2 proteins and MROD activities. URO accumulation was increased in cultures expressing either ortholog when supplemented with 5-aminolevulinic acid, the porphyrin precursor. Cells expressing mouse CYP1A2 produced more URO than cells expressing human CYP1A2. The results indicate that human CYP1A2 can support URO accumulation in hepatoma cells and thus may play a role in human PCT.
authors.affiliation: VA Medical Center, 215 N. Main Street, White River Junction, VT 05009, USA. ralph.c.nichols@dartmouth.edu
authors.forename: Ralph C
authors.initials: RC
authors.lastname: Nichols
authors.forename: Sandra
authors.initials: S
authors.lastname: Cooper
authors.forename: Heidi W
authors.initials: HW
authors.lastname: Trask
authors.forename: Nadia
authors.initials: N
authors.lastname: Gorman
authors.forename: Timothy P
authors.initials: TP
authors.lastname: Dalton
authors.forename: Daniel W
authors.initials: DW
authors.lastname: Nebert
authors.forename: Jacqueline F
authors.initials: JF
authors.lastname: Sinclair
authors.forename: Peter R
authors.initials: PR
authors.lastname: Sinclair
mesh_terms: D000622:Aminolevulinic Acid / Q000494:pharmacology; D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000378:metabolism*; D019388:Cytochrome P-450 CYP1A2 / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D006801:Humans; D015151:Immunoblotting; D051379:Mice; D010088:Oxidoreductases / Q000378:metabolism; D017119:Porphyria Cutanea Tarda / Q000201:enzymology* / Q000378:metabolism; D014162:Transfection; D014407:Tumor Cells, Cultured; D014578:Uroporphyrins / Q000378:metabolism*
chemical_list: D014578:Uroporphyrins; D000622:Aminolevulinic Acid; D003577:Cytochrome P-450 Enzyme System; D010088:Oxidoreductases; C076307:methoxyresorufin-O-demethylase; D019388:Cytochrome P-450 CYP1A2