Biophysical aspects of P-glycoprotein-mediated multidrug resistance.

In the 45 years since Burchenal's observation of chemotherapeutic drug resistance in tumor cells, many investigators have studied the molecular basis of tumor drug resistance and the phenomenon of tumor multidrug resistance (tumor MDR). Examples of MDR in microorganisms have also become topics of intensive study (e.g., Plasmodium falciparum MDR and various types of bacterial MDR) and these emerging fields have, in some cases, borrowed language, techniques, and theories from the tumor MDR field. Serendipitously, the cloning of MDR genes overexpressed in MDR tumor cells has led to elucidation of a large family of membrane proteins [the ATP-binding cassette (ABC) proteins], an important subset of which confer drug resistance in many different cells and microorganisms. In trying to decipher how ABC proteins confer various forms of drug resistance, studies on the structure and function of both murine and human MDR1 protein (also called P-glycoprotein or P-gp) have often led the way. Although various theories of P-gp function have become popular, there is still no precise molecular-level description for how P-gp overexpression lowers intracellular accumulation of chemotherapeutic drugs. In recent years, controversy has developed over whether the protein protects cells by translocating drugs directly (as some type of drug pump) or indirectly (through modulating biophysical parameters of the cell). In this ongoing debate over P-gp function, detailed consideration of biophysical issues is critical but has often been neglected in considering cell biological and pharmacological issues. In particular, P-gp overexpression also changes plasma membrane electrical potential (delta psi zero) and intracellular pH (pHi), and these changes will greatly affect the cellular flux of a large number of compounds to which P-gp overexpression confers resistance. In this chapter, we highlight these biophysical issues and describe how delta psi zero and pHi may in fact be responsible for many MDR-related phenomena that have often been hypothesized to be due to direct drug translocation (e.g., drug pumping) by P-gp.