P-glycoproteins span the plasma membrane and are capable of transporting drugs out of cells, thus lowering the intracellular drug concentrations to non toxic levels. To address this issue, we have chosen to study the interaction between P-glycoproteins and steroids. Steroid hormones are vital signaling molecules that are released by specific tissues to circulate throughout the body. These molecules diffuse into cells where they activate gene regulatory proteins. Steroids, in particular the class called glucocorticoids, are important elements in the treatment of cancers such as leukemias and lymphomas.
Glucocorticoids induce cell death in lymphoid cells.
We have developed definitive evidence that P-glycoproteins can transport a clinically relevant subset of glucocorticoid hormones and convey increased steroid resistance to murine lymphoma cells in which the proteins are expressed. Our recent work has established that only the mdr1 P-glycoprotein is capable of transporting glucocorticoids. Since the two proteins also exhibit differential tissue expression, the results support the hypothesis that the mdr1 and mdr3 P-glycoproteins serve alternative roles in regulating the intracellular concentrations of endogenous substances such as steroids. Thus, P-glycoproteins may normally act to provide more than just a protective mechanism to xenobiotic compounds. While the mdr1 P-glycoprotein can transport a wide variety of dissimilar compounds, it can also exhibit significant selectivity within the members of a single class of drugs.