Dr. Henry Strobel, Professor

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cytochrome p450 dependent drug metabolism

Cytochrome P450 Dependent Drug MetabolismCytochromes 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.

Selected References

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.

Kalsotra, A., Turman, C.M., Kikuta, Y., and Strobel. H.W.: Expression and Characterization of Human Cytochrome P450 4F11: Putative Role in the Metabolism of Therapeutic Drugs and Eicosanoids, Toxicology and Applied Pharmacology, 199: 295-304, 2004.

Chinta, S.J., Kommaddi, R.P., Turman, C.M., Strobel, H.W., and Ravindranath, V. Constitute Expression and Localization of Cytochrome P4501A1 in Rat and Human Brain: Presence of Splice Variant Form in Human Brain.  Journal of Neurochemistry, 93:724-736, 2005.

Turman, C.M., Hatley, J.M., Ryder, D.J., and Strobel, H.W. Alternative Splicing Within the Human Cytochrome P450 Superfamily with an Emphasis on Brain: The Convolution Continues. Expert Opinion on Drug Metabolim and Toxicology, 2: 399-418, 2006.