title: Molecular modelling of CYP2E1 enzymes from rat, mouse and man: an explanation for species differences in butadiene metabolism and potential carcinogenicity, and rationalization of CYP2E substrate specificity.
abstract: Molecular modelling of substrates of cytochrome P4502E1 (CYP2E1) within the putative active site region of CYP2E1 constructed from the CYP102 crystal structure is reported. Structural characteristics of CYP2E1 substrates, such as molecular size, energy levels and polarity, calculated via molecular orbital procedures provide correlations with toxicity and carcinogenicity; and species differences in CYP2E1-mediated metabolism are rationalized in terms of interactions with putative active site amino acid residues, including Thr-437 and Phe-181. In particular, the activation of buta-1,3-diene can be explained by active site modelling with CYP2E1 enzymes sequenced from rat, mouse and man, where there is a non-conservative change T437H between rodent and human isozymes, together with a conservative change I438V between mouse and rat CYP2E1.
authors.affiliation: Molecular Toxicology Group, Centre for Toxicology, School of Biological Sciences, University of Surrey, Guildford, UK.
authors.forename: D F
authors.initials: DF
authors.lastname: Lewis
authors.forename: M G
authors.initials: MG
authors.lastname: Bird
authors.forename: D V
authors.initials: DV
authors.lastname: Parke
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D002070:Butadienes / Q000737:chemistry / Q000378:metabolism* / Q000633:toxicity; D002273:Carcinogens / Q000737:chemistry / Q000378:metabolism / Q000633:toxicity*; D003198:Computer Simulation; D003460:Crystallization; D019392:Cytochrome P-450 CYP2E1 / Q000737:chemistry / Q000378:metabolism*; D004852:Epoxy Compounds / Q000378:metabolism; D006801:Humans; D006838:Hydrocarbons / Q000737:chemistry / Q000378:metabolism / Q000633:toxicity*; D007527:Isoenzymes / Q000737:chemistry / Q000378:metabolism; D051379:Mice; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010084:Oxidation-Reduction; D010649:Phenylalanine / Q000378:metabolism; D051381:Rats; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid; D013045:Species Specificity; D013329:Structure-Activity Relationship; D013379:Substrate Specificity; D013912:Threonine / Q000378:metabolism
chemical_list: D002070:Butadienes; D002273:Carcinogens; D004852:Epoxy Compounds; D006838:Hydrocarbons; D007527:Isoenzymes; D013912:Threonine; D010649:Phenylalanine; D019392:Cytochrome P-450 CYP2E1