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 has been shown that P-gp transports various kinds of anti-cancer agents as well as hydrophobic chemicals. Although P-gp is also expressed in normal human tissues, such as liver, kidney, and adrenal gland, its function 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 tissue contains large amount of compounds which inhibit the transporting activity of P-gp. We purified such compounds from the adrenal gland by monitoring the ability to enhance the accumulation of [3H]vincristine in MDR cells. Two major compounds were purified and identified as progesterone and pregnenolone by nuclear magnetic resonance (NMR) analysis. Progesterone was the most potent and abundant compound that inhibited the transporting activity of P-gp among the compounds extracted from bovine adrenal gland with methanol. We also found that six authentic progesterone metabolites in the 5 beta-metabolic pathway but none in the 5 alpha-metabolic pathway were able to enhance the accumulation of [3H]vincristine in MDR cells and to inhibit [3H]azidopine photolabeling of P-gp in the adrenal gland. These results indicate that some progesterone metabolites can interact with P-gp and that stereoisomerism around carbon 5 of the progesterone metabolites is important for them to be recognized by P-gp.
Ichikawa-Haraguchi
M
M
Cancer Research Institute, Faculty of Medicine, Kagoshima University, Japan.
Sumizawa
T
T
Yoshimura
A
A
Furukawa
T
T
Hiramoto
S
S
Sugita
M
M
Akiyama
S
S
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000311:Adrenal Glands / Q000737:chemistry / Q000378:metabolism*; D000818:Animals; D001665:Binding Sites; D001692:Biological Transport; D002352:Carrier Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism*; D002417:Cattle; D004351:Drug Resistance / Q000235:genetics; D006801:Humans; D008562:Membrane Glycoproteins / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism*; D010641:Phenotype; D011284:Pregnenolone / Q000302:isolation & purification / Q000494:pharmacology*; D011374:Progesterone / Q000302:isolation & purification / Q000494:pharmacology*; D014407:Tumor Cells, Cultured; D014747:Vinblastine / Q000378:metabolism; D014750:Vincristine / Q000378:metabolism
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D002352:Carrier Proteins; D008562:Membrane Glycoproteins; D011374:Progesterone; D014750:Vincristine; D014747:Vinblastine; D011284:Pregnenolone