Uniformed Services University of the Health Sciences
Department of Biochemistry and Molecular Biology
4301 Jones Bridge Road, C1094
Bethesda, Maryland 20814-4799
Phone: (301) 295-3449
Fax: (301) 295-3512
Lab: (301) 295-9414
Human MultidrugTransporter: Mode of Action and Functional Regulation.
The effectiveness of anti-microbial and anti-cancer chemotherapy largely depends on the ability of thetherapeutic agents to reach their sites of action. Following administration, the fate of a drug molecule depends on how well it is absorbed from its site of administration, its distribution pattern, the extent and nature of its biotransformation, and on the efficiency by which it is excreted. Even when these obstacles are surpassed, thetherapeutic potency of a drug could be profoundly affected by occurrence of intrinsic as well as acquired drug resistance in the target cells. Thus, strategic development of chemotherapeutic drugs has to continuously battle against poor bioavailability and occurrence of drug resistance. The role of the human multidrug transporter P-glycoprotein (Pgp) in both of these phenomena is rapidly unfolding. Functionally, Pgp is an ATP-dependent efflux pump for an inordinately widerange of structurally unrelated hydrophobic drugs including anti-cancer and anti-HIV agents. In order to retain thetherapeutic effectiveness of chemotherapeutic agents, a major effort is underway to selectively inhibit the function of Pgp in tumor cells as well as in certain normal tissues. Although random screening of natural products and synthetic libraries have shown some promise, a better understanding of the mechanism of Pgp-mediated drug transport is necessary for developing inhibitors with improved efficacy.
Research goals of our laboratory are directed towards 1) elucidation of the molecular mechanism involved in coupling of ATP hydrolysis to drug translocation by Pgp, 2) characterization of its functional regulation by pharmacological agents as well as endogenous molecules and 3) identification of novel therapeutic targets within the protein. We use a baculovirus mediated heterologous expression system for generation and biochemical characterization of recombinant Pgp molecules. Stable and transient transfectants of mammalian cell lines are used for assessing transport properties of the recombinant proteins.
Fong, W. F., Wan, C. K., Zhu, G. Y., Chattopadhyay, A., Dey S., Zhao, Z., and Shen, X. L.. (2007) Schisandrol A from Schisandra chnensis reverses P-glycoprotein-mediated multidrug resistance by affecting Pgp-substrate complexes. Planta Medica, 73: 212-220.
Wan, C. K., Zhu, G. Y., Shen, X. L., Chattopadhyay, A., Dey, S., and Fong, W. F. (2006) Gomisin A alters substrate interaction and reverses P-glycoprotein mediated multidrug resistance in HepG2-DR cells. Biochemical Pharmacology, 72(7): 824-837.
Maki, N., and Dey, S. (2006) Biochemical and pharmacological properties of an allosteric modulator site of human P-glycoprotein. Biochemical Pharmacology 72:145-155 Maki, N., Moitra, K., Ghosh, P., and Dey, S. (2006) Allosteric modulation bypasses requirement for ATP hydrolysis in regenerating low-affinity transition state conformation of human P-glycoprotein. Journal of Biological Chemistry . 281(16): 10699-10777
Ghosh, P., Moitra, K., Maki, N., and Dey, S. (2006) Allosteric modulation of the human P-glycoprotein involves conformational changes mimicking catalytic transition intermediates. Archives of Biochemistry and Biophysics . 450 (1): 100-112.
Maki, N., Moitra, K., Silver, C., Ghosh, P., Chattopadhyay, A. K., and Dey, S. (2006) Modulator induced interference in functional cross talk between the substrate- and the ATP- sites of human P-glycoprotein. Biochemistry 45: 2739-2751
Maki, N., Hafkemeyer, P., and Dey, S. (2003). Allosteric modulation of human P-glycoprotein: Inhibition of transport by preventing substrate translocation and dissociation. Journal of Biological Chemistry. 278(20):18132-18139.
Dey, S. (2002) Biricodar (Vertex Pharmaceuticals). Current Opinion in Investigational Drugs, Vol. 3(5): 818-823.
Saibal Dey, Ph.D. (Principal Investigator)
Karobi Moitra, Ph.D. (Postdoctoral Fellow)
Debjani Mandal, Ph.D. (Postdoctoral Fellow)
Jun Chen, Ph.D. (Postdoctoral Fellow)
Anita Padliya (Technical Assistant)
Arnab Sarker (Summer Student)
Nazli Maki, Ph.D. (Postdoctoral Fellow)
Apurba Chattopadhyay, Ph.D. (Postdoctoral Fellow)
Ruma Dey, Ph.D. (Postdoctoral Fellow)
Pratiti Ghosh, Ph.D. (Postdoctoral Fellow)
Cara Silver (Summer Student)
NIH R01 Grant GM067926-01 (Project Period: 05/01/2003 - 04/31/2008)
USUHS Exploratory Grant H071HG ( Project Period: 08-01/2004 - 09/30/2007)