Bourgeois S, Gruol D J, Newby R F, Rajah F M
Salk Institute for Biological Studies Regulatory Biology Laboratory, San Diego, California 92186-5800.
Mol Endocrinol. 1993 Jul;7(7):840-51. doi: 10.1210/mend.7.7.8105374.
A variant, MS23, of murine thymoma W7 cells, previously selected for its resistance to low concentrations of dexamethasone, is cross-resistant to unrelated drugs such as puromycin and colchicine. We report here that transcription of the mouse mdr1 gene is activated and P-glycoprotein is expressed in MS23 cells. Moreover, additional variants with increased resistance to dexamethasone and other drugs can be isolated from MS23 by stepwise selections in dexamethasone and colchicine. In one such variant (S7CD-5), the mdr1 gene is amplified and the mdr protein overexpressed. These variants have classical mdr characteristics: they accumulate reduced concentrations of drugs (including dexamethasone), and both drug sensitivity and intracellular accumulation can be restored by verapamil. The variants are most resistant to glucocorticoids with both 11- and 17-hydroxyl groups. The results indicate that we have identified a new form of glucocorticoid resistance, one associated with expression of the mouse mdr1 P-glycoprotein.
小鼠胸腺瘤W7细胞的一个变种MS23，先前因其对低浓度地塞米松具有抗性而被筛选出来，它对诸如嘌呤霉素和秋水仙碱等不相关药物也具有交叉抗性。我们在此报告，小鼠mdr1基因的转录在MS23细胞中被激活，并且P-糖蛋白得以表达。此外，通过在地塞米松和秋水仙碱中进行逐步筛选，可以从MS23中分离出对地塞米松和其他药物抗性增强的其他变种。在其中一个这样的变种（S7CD-5）中，mdr1基因被扩增，mdr蛋白过度表达。这些变种具有典型的mdr特征：它们积累的药物（包括地塞米松）浓度降低，并且维拉帕米可以恢复药物敏感性和细胞内积累。这些变种对同时具有11-羟基和17-羟基的糖皮质激素最具抗性。结果表明，我们已经鉴定出一种新的糖皮质激素抗性形式，一种与小鼠mdr1 P-糖蛋白的表达相关的抗性形式。
