title: Molecular orbital studies of oxygen activation and mechanisms of cytochromes P-450-mediated oxidative metabolism of xenobiotics.
abstract: Molecular dimensions and molecular orbital calculations of the electronic structures of 56 substrates, inhibitors and inducers of the cytochromes P-448 and other families of the cytochromes P-450 are reported. Substrates of the cytochromes P-448 are shown to be planar molecules with relatively large values of area/depth2, and to have electronic structures with relatively low values for delta E, the difference in energy between the frontier orbitals (E(LEMO)- E(HOMO)). Substrates of other families of the cytochromes P-450 are globular molecules, with relatively low values of area/depth2 and relatively high values of delta E. Molecular orbital calculations of the active oxygen species, singlet oxygen and superoxy anion, have also been made. Singlet oxygen is a poor electron donor (low values of E(HOMO)) but a good electron acceptor (low values of E(LEMO)), whereas superoxy anion is a good electron donor and a poor electron acceptor. Cytochrome P-448 substrates, which are good electron donors, would preferentially accept singlet oxygen, a good electron acceptor; substrates of the other families of cytochrome P-450, which are less effective electron donors, would preferentially accept superoxy anion, a good electron donor, although substrates of both cytochromes P-448 and other P-450s may accept both species of active oxygen. Together with recent published evidence, these data provide a greater understanding of the mode of activation of oxygen by the various families of the cytochromes P-450, and to the insertion of active oxygen into the substrates. Mechanisms are proposed for the oxygenation of substrates, namely, epoxidation involving singlet oxygen and hydroxylation by superoxy anion. Finally, a detailed explanation of the cytochrome P-450 cycle is discussed, and mechanisms of the different types of oxidative metabolism are presented.
authors.affiliation: Department of Biochemistry, University of Surrey, Guildford, U.K.
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: D019388:Cytochrome P-450 CYP1A2; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D003580:Cytochromes / Q000378:metabolism*; D008956:Models, Chemical; D015394:Molecular Structure; D010084:Oxidation-Reduction; D010100:Oxygen / Q000378:metabolism; D011789:Quantum Theory; D013379:Substrate Specificity; D015262:Xenobiotics / Q000032:analysis* / Q000378:metabolism
chemical_list: D003580:Cytochromes; D015262:Xenobiotics; D003577:Cytochrome P-450 Enzyme System; C017170:Cyp1a2 protein, rat; D019388:Cytochrome P-450 CYP1A2; D010100:Oxygen