Cytochrome P450 Dependent Drug Metabolism

Cytochromes P450 catalyze a variety of critical reactions including aspects of cholesterol metabolism leading to the production of steroid hormones and bile acids, fatty acid oxidation, the metabolism of vitamin D, the activation/ deactivation of the great majority of therapeutic drugs and the activation/deactivation of many significant environmental toxicants. Over 600 genes have been sequenced and members of the P450 super family have been shown in all phyla and kingdoms. In the mammalian species studied, the current estimates posit between 40 and 60 forms in each organism. The distribution of forms among the tissues and organs of a given mammalian organism is, however, not uniform. For instance, the cytochrome P450 isoform content of liver is different from that of kidney or lung or brain. This means that the product profiles produced from a single compound may be radically different from organ to organ. Thus, differential distribution of cytochromes P450 is consistent with the fact that a "carcinogen" requiring activation by "P450" may cause cancer in one organ but not in another.

We focus on defining the role and regulation of CYP P450 during its metabolism of endogenous compounds drugs and carcinogens in brain, liver, lung and colon. We also study the distribution of CYP isoforms in various regions of brain to understand the response of brain tissue to physical injury as well as in the treatment of depression, epilepsy and schizophrenia. In this area we have cloned six new forms of P450 and are studying the mechanism of action, regulation of P450 expression in brain and lung, site of metabolism and metabolite pro-files of antidepressant, antipsychotic and antiepileptic drugs as well as prostaglandins and leukotriene.

Active Site Projection of CYP1A1 showing
region involved in O₂ and substrate binding

Antonovic, L., Hodek, P., Smrcek, S., Novak, P., Sulc, M., and Strobel, H.W.: Heterobifunctional Photoaffinity Probes for Cytochrome P450 2B. Arch. of Biochem. Biophysics. 370: 208-215, 1999.

Cvrk, T. and Strobel, H.W. : Photoaffinity Labeling of Cytochrome P4501A1 with Azidocumene: Identification of Cumene Hydroperoxide Binding Region. Arch. Biochem. Biophysics 349:95-104, 1998.

Kawashima, H., Kusunose, E., Thompson, C.M. and Strobel, H.W.: Protein Expression, Characterization and Regulationof CYP4F4 and CYP4F5 Cloned from Rat Brain. Arch. Biochem. Biophysics. 347:148-154, 1997.

Kawashima, H., Sequeira, D.J., Nelson, D.R. and Strobel, H.W.: Genomic cloning and protein expression of a novel rat brain cytochrome P450 CYP2D18 catalyzing imipramine N-demethylation. J. Biol. Chem. 271:28176-28180, 1996.