PROGESTERONE AND ITS METABOLITES - THE POTENT INHIBITORS OF THE TRANSPORTING ACTIVITY OF P-GLYCOPROTEIN IN THE ADRENAL-GLAND

P-glycoprotein (P-gp) is a transmembrane glycoprotein responsible for the multidrug resistant (MDR) phenotype in various cancer cells. It ha s been shown that P-gp transports various kinds of anti-cancer agents as well as hydrophobic chemicals. Although P-gp is also expressed in n ormal human tissues, such as liver, kidney, and adrenal grand, its fun ction and transporting substrates in these tissues are still unknown. In previous work, we demonstrated that some compounds in human plasma modulate the transporting activity of P-gp. We also found that P-gp is expressed at a high level in the bovine adrenal gland and that this t issue contains large amount of compounds which inhibit the transportin g activity of P-gp. We purified such compounds from the adrenal gland by monitoring the ability to enhance the accumulation of [H-3]vincrist ine in MDR cells. Two major compounds were purified and identified as progesterone and pregnenolone by nuclear magnetic resonance (NMR) anal ysis. Progesterone was the most potent and abundant compound that inhi bited the transporting activity of P-gp among the compounds extracted from bovine adrenal gland with methanol. We also found that six authen tic progesterone metabolites in the 5 beta-metabolic pathway but none in the 5 alpha-metabolic pathway were able to enhance the accumulation of [H-3]vincristine in MDR cells and to inhibit [H-3]azidopine photol abeling of P-gp in the adrenal gland. These results indicate that some progesterone metabolites can interact with P-gp and that stereoisomer ism around carbon 5 of the progesterone metabolites is important for t hem to be recognized by P-gp.