Research Interests
Xenobiotic metabolism, novel reactive intermediates,
interactions of genotoxic agents
The rate of metabolism of drugs and other foreign chemicals (xenobiotics), and the specific enzymes and pathways involved in this metabolism, are major determinants of their biological effects. Variability in the expression of key xenobiotic-metabolizing enzymes is a major contributor to inter-individual variation in the therapeutic and toxic effects of chemicals. We are developing and validating a novel drug cocktail as a probe for phenotyping human subjects for key xenobiotic-metabolizing enzyme activities. With this approach five drugs are administered to human volunteers and blood and urine samples obtained and analyzed for particular drug metabolites.
These analyses utilize HPLC, GC, and immunoassays. The levels of these specific metabolites provide a measure of the activities of several cytochrome P450s (CYP1A2, 2C9, 2D6, and 3A4) as well as other enzymes associated with xenobiotic metabolism. Beyond this baseline phenotyping, we also are applying this approach to studying the modulation of xenobiotic-metabolizing enzymes in humans. Drugs or other xenobiotics may compete for the same enzyme, decreasing the net rate of metabolism. Other compounds may induce certain xenobiotic-metabolizing enzymes, resulting in significant increases in metabolic rate. Either of these alterations can cause significant changes in therapeutic and toxicologic responses following drug or chemical exposure.
By determining the effects of diet, nutritional supplements, or other drugs or chemicals on the metabolism of the drug probe we can predict drug-drug or other interactions which could adversely affect an individual's response to therapy. Two projects are currently underway to determine if dietary supplements alter prescription drug metabolism. In one of these projects we are studying a supplement with supposed cancer chemopreventive activity, and in the other study are targeting two widely-used herbal products.
The findings from these studies can be of immediate clinical value in that significant alterations of xenobiotic-metabolizing enzymes must be taken into consideration when advising patients about use of these supplements. The other application is that any observed alterations in xenobiotic-metabolizing enzyme activities in these human studies will be followed by in vitro work and experiments in animal models to characterize the mediators and mechanisms of the resultant alterations.
Reed, G.A., Wilson, A.M., and Padgitt, J.K.: Estradiol metabolism by rat liver microsomes from strains differing in susceptibility to mammary carcinogenesis. In: Hormonal Carcinogenesis III (J.J. Li, J.R. Daling, S.A. Li, eds.), pp. 451-455, Springer-Verlag, New York, 2001. Wilson, A.M. and Reed, G.A.: Predominant 4-hydroxylation of estradiol by constitutive cytochrome P450s in the ACI rat liver. Carcinogenesis 22: 257-263, 2001.
Van Veldhuizen, P.J., Reed, G.A., Arvind, A., Baranda, J., Taylor, S., and Williamson, S.: A phase 1 study of docetaxel and ketoconazole in advanced hormone refractory prostate cancer. Proceedings, American Society for Clinical Oncology, 2452, 2002.
Reed, G., Smith, H., Peterson, K., Wesselius, L., Plautz, M., Bailey, K., Crowell, J., Hurwitz, A. Selenomethionine and vitamin E in smokers: A Phase I study of a potential chemopreventive regimen. Toxicol. Sciences, in press, 2003.
Reed, G., Moreland, S., Peterson, K., Smith, H., Crowell, J., and Hurwitz, A. Altered microsomal enzyme activities in women treated with indole-3-carbinol. Proceedings, American Association for Cancer Research, in press, 2003.
Gregory A. Reed, Ph.D
.Associate Professor
Department of Pharmacology, Toxicology and Therapeutics
The University of Kansas Medical Center
MS1018
3901 Rainbow Boulevard
Kansas City, KS 66160
Phone: (913) 588-7513
Fax: (913) 588-7501
E-Mail: greed@kumc.edu
Curriculum Vitae in PDF Format
Updated 8/9/05
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The University of Kansas Medical Center