title: Molecular modelling of cytochrome CYP1A1: a putative access channel explains differences in induction potency between the isomers benzo(a)pyrene and benzo(e)pyrene, and 2- and 4-acetylaminofluorene.
abstract: The present studies were undertaken to provide a rationale for the observation that benzo(a)pyrene and 2-acetylaminofluorene induce the hepatic CYP1A1 protein, whereas their non-carcinogenic isomers benzo(e)pyrene and 4-acetylaminofluorene are, at best, relatively very weak inducers. Using amino acid sequence alignment, a molecular model of the CYP1A1 was constructed by analogy to CYP101, the bacterial protein for which the 3-dimensional structure is known from X-ray crystallographic analysis. The putative structure of the active site of the CYP1A1 protein shows the presence of two phenylalanine residues preferentially aligned in parallel orientation, presumably functioning as a 'sieve' for planar molecules, the established substrates of CYP1A1. The molecular dimensions of this putative access channel show a width and depth of 8.321 and 3.261 A, respectively. The width of 4-acetylaminofluorene, 8.794 A, and benzo(e)pyrene, 9.153 A, precludes their passage through this channel access in contrast to benzo(a)pyrene and 2-acetylaminofluorene having a width of 7.150 and 5.283 A, respectively, explaining their difference in CYP1A1 induction potential.
authors.affiliation: Division of Toxicology, School of Biological Sciences, University of Surrey, Guildford, UK.
authors.forename: D F
authors.initials: DF
authors.lastname: Lewis
authors.forename: C
authors.initials: C
authors.lastname: Ioannides
authors.forename: D V
authors.initials: DV
authors.lastname: Parke
mesh_terms: D015073:2-Acetylaminofluorene / Q000031:analogs & derivatives* / Q000737:chemistry* / Q000378:metabolism; D001564:Benzo(a)pyrene / Q000737:chemistry* / Q000378:metabolism; D001580:Benzopyrenes / Q000737:chemistry* / Q000378:metabolism; D002273:Carcinogens / Q000737:chemistry* / Q000378:metabolism; D019388:Cytochrome P-450 CYP1A2; D003580:Cytochromes / Q000096:biosynthesis / Q000737:chemistry* / Q000378:metabolism; D004790:Enzyme Induction; D008958:Models, Molecular
chemical_list: D001580:Benzopyrenes; D002273:Carcinogens; D003580:Cytochromes; D001564:Benzo(a)pyrene; C026487:benzo(e)pyrene; D015073:2-Acetylaminofluorene; C017170:Cyp1a2 protein, rat; D019388:Cytochrome P-450 CYP1A2; C028676:4-acetylaminofluorene