Webster Jeanette I, Carlstedt-Duke Jan
Department of Medical Nutrition, Karolinska Institute, Novum, Huddinge Hospital, Sweden.
J Steroid Biochem Mol Biol. 2002 Nov;82(4-5):277-88. doi: 10.1016/s0960-0760(02)00227-3.
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.
糖皮质激素抵抗是许多疾病治疗中的一个问题。参与调节糖皮质激素反应的一个可能因素是糖皮质激素从细胞中输出。已有研究表明，ABC家族成员多药耐药蛋白1（MDR1，ABCB1）能够转运一些糖皮质激素。本文使用一种小鼠细胞系LMCAT，在该细胞系中糖皮质激素反应可被多药耐药蛋白抑制剂调节。糖皮质激素可分为三类。第一类是那些由Abcb1a/Abcb1b转运蛋白转运且其转运可被ABCB1活性抑制剂抑制的糖皮质激素。通过这些药物对罗丹明外排的抑制检测到功能性Abcb1a/Abcb1b，并在这些细胞中检测到Abcb1a和Abcb1b的mRNA。第二类是那些不被转运的糖皮质激素。最后一类是由Abcc1a转运蛋白转运的糖皮质激素。用丙磺舒处理可阻断这些细胞中钙黄绿素的转运，表明存在功能性Abcc1a转运蛋白。在这些细胞中也检测到了Abcc1a mRNA。因此，本文深入探讨了细胞中糖皮质激素转运的机制，并证明了Abcb1a/Abcb1b和Abcc1a对糖皮质激素的两种独立转运机制具有多样性，且具有各自的类固醇特异性模式。
