title: The K-region trans-8,9-diol does not significantly contribute as an intermediate in the metabolic activation of dibenzo[a,l]pyrene to DNA-binding metabolites by human cytochrome P450 1A1 or 1B1.
abstract: Metabolic activation of the K-region trans-8,9-diol of the highly carcinogenic hexacyclic aromatic hydrocarbon dibenzo[a,l]pyrene (DB[a,l]P) by human cytochrome P-450 (P450) 1A1 and 1B1 was investigated in Chinese hamster V79 cell lines expressing human P450 1A1 or 1B1. P450 1A1 and 1B1 are the major P450s involved in metabolic activation of polycyclic aromatic hydrocarbons in human cells. The major DNA adducts formed by metabolism of DB[a,l]P in cultures expressing P450 1A1 or 1B1 resulted mainly from the fjord region (-)-anti-DB[a,l]P-11,12-diol 13,14-epoxide [(-)-anti-DB[a,l]PDE] and, to a lesser extent, (+)-syn-DB[a,l]PDE. In V79 cells expressing human P450 1A1, high amounts of as yet unidentified highly polar DNA adducts are formed in addition to the DNA adducts derived from DB[a,l]PDEs. Human P450 1A1 has been found to metabolize DB[a,l]P on its K-region to the trans-8,9-diol, and it has been proposed that the DNA binding of the parent compound in P450 1A1-expressing tissues may be partially mediated by activation of the K-region trans-8,9-diol to form bis-diol epoxides. V79 cells expressing human P450 1A1 or 1B1 formed only low amounts of DNA adducts after treatment with high doses of the K-region trans-8,9-diol. None of the adducts formed were identical to the main adducts formed in the same cell lines by metabolic activation of DB[a,l]P or (-)-DB[a,l]P-trans-11,12-diol. These results demonstrate that the K-region trans-8,9-diol does not significantly contribute to the genotoxicity of the very potent carcinogen DB[a,l]P in human cells or tissues expressing P450 1A1 or 1B1.
authors.affiliation: Department of Environmental and Molecular Toxicology, Oregon State University, Corvallis 97331, USA.
authors.forename: A
authors.initials: A
authors.lastname: Luch
authors.forename: S
authors.initials: S
authors.lastname: Kishiyama
authors.forename: A
authors.initials: A
authors.lastname: Seidel
authors.forename: J
authors.initials: J
authors.lastname: Doehmer
authors.forename: H
authors.initials: H
authors.lastname: Greim
authors.forename: W M
authors.initials: WM
authors.lastname: Baird
mesh_terms: D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases; D001580:Benzopyrenes / Q000493:pharmacokinetics*; D001711:Biotransformation; D002273:Carcinogens / Q000493:pharmacokinetics*; D002460:Cell Line; D006224:Cricetinae; D003412:Cricetulus; D019363:Cytochrome P-450 CYP1A1 / Q000378:metabolism*; D065633:Cytochrome P-450 CYP1B1; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D004247:DNA / Q000378:metabolism*; D018736:DNA Adducts / Q000378:metabolism*; D006801:Humans; D011994:Recombinant Proteins / Q000378:metabolism; D014162:Transfection
chemical_list: D001580:Benzopyrenes; D002273:Carcinogens; D018736:DNA Adducts; D011994:Recombinant Proteins; D004247:DNA; D003577:Cytochrome P-450 Enzyme System; D001189:Aryl Hydrocarbon Hydroxylases; C585496:CYP1B1 protein, human; D019363:Cytochrome P-450 CYP1A1; D065633:Cytochrome P-450 CYP1B1; C041517:dibenzo(a,l)pyrene