Joseph Bentz, PhD
Office: PISB 416
Lab: PISB 402
Lab Phone: 215.895.6891
Specialization: Biophysics of Cell Membrane Function - Membrane Transport by Multidrug Resistance Proteins, chanisms of Membrane Fusion, Peptide/Protein-Membrane Interactions
- BS, Chemistry, Reed College
- PhD, Biophysical Sciences, SUNY at Buffalo
Mass action kinetic modeling of membrane transport networks:
Our primary project is the study of Multidrug resistance transporters. We have long-standing collaboration with GlaxoSmithKline to develop a quantitative kinetic model of transcellular transport mediated by the multidrug resistance protein P-gp. This transporter is found in many human tissues, where it is responsible for inhibiting uptake of foreign molecules, e.g. the colon, the kidney, the liver, gonads a nd the b picks up amphiphilic compounds from the inner apical membrane, which faces the “outside” world, and uses the energy of ATP hydrolysis to eject the compound back to the “outside” world. However, many cancer cells have acquired or amplified the gene for this transporter since it will also inhibit their uptake of chemotherapeutic agents. It is thought that this acquired resistance is responsible for much of the failure of cancer chemotherapy. P-gp has 12 transmembrane domains and a very large range of substrates, which has complicated the elucidation of its binding and active sites. Our approach is to create a rigorous analysis of its transport kinetics, which will allow a clear focus on the how compound structure and transporter mutations affect elementary rate constants of transport for this protein. This can guide more precise structure-function relationships for P-gp and hopefully effective inhibitors.
Academic and Professional Positions
- 1981-82 Cancer Research Scientist II - Department of Experimental Pathology, Ro tute, Buffalo, New York
- 1982-88 Assistant Professor in Residence
- 1988-89 Associate Professor in Residence - Departments of Pharmacy & Pharmaceutical Chemistry, School of
Pharmacy, University of California, San Francisco, California
- 1989-95 Associate Professor
- 1992-95 Assistant Department Head
- 1995-98 Departmennt Professor - Department of Biology, College Of Arts & Sciences, Drexel University,
Kinetic identification of membrane transporters that assist transcellular transport of many P-gp substrates
through a confluent monolayer of cells expressing hMDR1.
AA Lumen, L Li, J Li, AD Owen, IJ Hidalgo, H Ellens & J Bentz. Drug Metab. Disp. submitted
Fitt ing the of P-gp mediated transport across the hMDR1-MDCK confluent cell monolayer using a Particle Swarm
algorithm and establishing the functional properties of other substrate-specific transporters.
D Agnani, P Acharya, E Martinez, T Tran, F Abraham, F Tobin, H Ellens & J Bentz. Submitted
If the KI is defined by the free energy of binding to P-gp, what kinetic parameters define the IC50 for the
MDCKII-hMDR1 confluent cell monolayer?
AA Lumen, P Acharya, JW Polli, A Ayrton, H Ellens & J Bentz. Drug Met Disp, 38:260-9