A group of closely related enzymes involved in the oxidation of many drugs and foreign substances are the so-called mixed function monoxygenases, known collectively as the cytochrome P-450's. The presence of these enzymes in living oganisms, both quantitatively and qualitatively, is highly influenced by numerous factors, such as species, sex, age, environment, nutritional status, and exposure to foreign compounds. Thus, it appears that the responsiveness of these enzymes allows the organism to adapt to its enviroment. One of the reactions catalyzed by the cytochrome P-450's is aromatic hydroxylation. It is known that arene oxides (epoxides) are intermediates formed in the process of introducing a hydroxyl group into an aromatic system. Where they are the first and obligatory intermediates in the hydroxylation reaction remains an open question. However, such arene oxides are generally highly reactive and are implicated in the cancer-causing effects of the polycyclic aromatic hydrocarbons.

 We are studying the mechanisms of the oxidative reactions catalyzed by purified forms of cytochrome P-450 as a function of both substrate and stereochemistry using isotope effects. Such studies require enyzme isolation and purification, the synthesis of structural analogs of optically active substrates labeled specifically with stable and radioactive isotopes, and the development of sensitive and specific assays using mass spectrometry or other techniques for quantifying product formation. It is hoped that such studies will lead to an understanding of the factirs that control the spectrum of reactivities displayed by these enzymes, and that they ultimately will provide a useful strategy for the prevention or avoidance of toxicity.

Recent Publications

Christian Audergon, Krishna. R. Iyer, Jeffrey. P. Jones, John. F. Darbyshire, and William. F. Trager, "Experimental and Theoretical Study of the Effect of Active-Site Constrained Motion on the Magnitude of the Observed Intramolecular Isotope Effect for the P450 101 Catalyzed Benzylic Hydroxylation of Isomeric Xylenes and 4,4'-Dimethylbiphenyl," J. Amer. Chem. Soc., 121, 41-47 (1999).

Robert L. Haining, Jeffrey P. Jones, Kirk R. Henne, Michael B. Fisher, Dennis R. Koop, William F. Trager, and Allan E. Rettie, "Enzymatic Determinants of the Substrate Specificity of CYP2C9: Role of B'-C Loop Residues in Providing the p-Stacking Anchor Site for Warfarin Binding," Biochemistry, 38, 3285-3292 (1999).

Luke L. Koenigs, Raimund M. Peter, Ann P. Hunter, Robert L. Haining, Allan E. Rettie, Thomas Friedberg, Michael P. Pritchard, Magang Shou, Thomas H. Rushmore, and William F. Trager, "Electrospray Ionization Mass Spectrometric Analysis of Intact Cytochrome P450: Identification of Tienilic Acid Adducts to P450 2C9," Biochemistry, 38, 2312-2319 (1999).

Minxia He, Kenneth R. Korzekwa, Jefferey P. Jones, Allan E. Rettie and William F. Trager, "Structural Forms of Phenprocoumon and Warfarin That Are Metabolized at the Active Site of CYP2C9," Arch. Biochem. Biophys.,372, 16-28 (1999).

David A. Erickson, Gary Mather, William F. Trager, Rene H. Levy and James J. Keirns, "Characterization of the In Vitro Biotransformation of the HIV-1 Reverse Transcriptase Inhibitor Nevirapine by Human Hepatic Cytochromes P-450," Drug Metab. Dipos., 27, 1488-1495 (1999).

Luke K. Lightning, Jeffrey P. Jones, Thomas Friedberg, Michael P. Pritchard, Magang Shou, Thomas H. Rushmore and William F. Trager, "Mechanism-Based Inactivation of Cytochrome P450 3A4 by L-754,394," Biochem., 39, 4276-4287 (2000).

Sreedhara Rao, Ron Aoyama, Michael Schrag, William F. Trager, Allan Rettie and Jeffrey P. Jones, "A Refined 3-Dimensional QSAR of Cytochrome P450 2C9: Computational Predictions of Drug Interactions," J. Med. Chem., 43, 2789-2796 (2000).

Minxia He, Allan E. Rettie, John Neal and William F. Trager, " Metabolism of Sulfinpyrazone Sulfide and Sulfinpyrazone by Human Liver Microsomes and cDNA-expressed P450s," Drug Metab. Dispos., 29, 701-711 (2001).

Kirk R. Henne, Michael B. Fisher, Krishna R. Iyer, Dieter H. Lang, William F. Trager and Allan E. Rettie, "Active Site Characteristics of CYP4B1 Probed with Aromatic Ligands," Biochemistry, 40, 8597-8605 (2001).

William F. Trager, "Oral Anticoagulants," In: Metabolic Drug Interactions, Chapter 29, ed. R. H. Levy, K. E. Thummel, W. F. Trager, P.D. Hansten and M. Eichelbaum, Lippincott, Williams & Wilkens, Philadephia, PA, p. 403-413 (2000).

Caiping Yao, Kent L. Kunze, Evan D. Kharasch, Y. Wang, William F. Trager, Isabelle Ragueneau and Rene H. Levy, "Fluvoxamine-Theophylline Interaction: Gap Between In Vitro and In Vivo Inhibition Constants Towards CYP1A2," Clin. Pharm., in press.

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This page last updated: June 17, 2002