Involvement of multidrug resistance proteins (MDR) in the modulation of glucocorticoid response.
Glucocorticoid resistance is a problem in the treatment of many diseases. One possible factor involved in the modulation of a glucocorticoid response is the export of glucocorticoids out of the cell. It has been shown that multidrug resistance protein 1 (MDR1, ABCB1), a member of the ABC family, is capable of transporting some glucocorticoids. This paper uses a mouse cell line, LMCAT in which the glucocorticoid response can be modulated by inhibitors of multidrug resistance proteins. Glucocorticoids fall into three categories. Firstly, those that are transported by an Abcb1a/Abcb1b transporter and whose transport can be inhibited by inhibitors of ABCB1 activity. Functional Abcb1a/Abcb1b was detected by inhibition of rhodamine efflux by these drugs and mRNA for Abcb1a and Abcb1b were detected in these cells. Secondly, those that are not transported. Finally, those that are transported by an Abcc1a transporter. Calcein transport out of these cells was blocked by treatment with probenecid indicating a functional Abcc1a transporter. Abcc1a mRNA was also detected in these cells. Thus, this paper provides insight into the mechanisms of glucocorticoid transport in cells and demonstrates a diversity of two independent mechanisms of transport of glucocorticoids by Abcb1a/Abcb1b and Abcc1a with individual patterns of steroid specificity.
Webster
Jeanette I
JI
Department of Medical Nutrition, Karolinska Institute, Novum, Huddinge Hospital, Sweden. jwebster@codon.nih.gov
Carlstedt-Duke
Jan
J
D018435:ATP Binding Cassette Transporter, Subfamily B / Q000235:genetics / Q000378:metabolism*; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics / Q000378:metabolism*; D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001692:Biological Transport; D002478:Cells, Cultured / Q000187:drug effects / Q000378:metabolism; D015500:Chloramphenicol O-Acetyltransferase / Q000378:metabolism; D017931:DNA Primers / Q000737:chemistry; D003907:Dexamethasone / Q000494:pharmacology*; D018432:Drug Resistance, Multiple; D005452:Fluoresceins / Q000378:metabolism; D005938:Glucocorticoids / Q000494:pharmacology*; D051379:Mice; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000235:genetics / Q000378:metabolism*; D011339:Probenecid / Q000494:pharmacology; D011401:Promoter Regions, Genetic; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012235:Rhodamines / Q000378:metabolism; D015533:Transcriptional Activation / Q000187:drug effects*
D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D018528:ATP-Binding Cassette Transporters; D015500:Chloramphenicol O-Acetyltransferase; D017931:DNA Primers; D003907:Dexamethasone; D005452:Fluoresceins; D005938:Glucocorticoids; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D011339:Probenecid; D012235:Rhodamines; C095122:multidrug resistance protein 3; C007740:fluorexon; C421109:multidrug resistance-associated protein 1