Effects of acid and lactone forms of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors on the induction of MDR1 expression and function in LS180 cells
Effects of acid and lactone forms of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors on the induction of MDR1 expression and function in LS180 cells
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DOI：
10.1016/j.ejps.2009.01.009
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发表时间：
2009-05-12
影响因子：
4.6
通讯作者：
Sakaeda, Toshiyuki
中科院分区：
文献类型：
--
作者：
Yamasaki, Daisuke;Nakamura, Tsutomu;Sakaeda, Toshiyuki
在本研究中，3-羟基-3-甲基戊二酰辅酶A还原酶（HMGCR）抑制剂，也称为他汀类药物，调节多药耐药蛋白1的基因表达和功能在人肠上皮LS 180细胞中检测了MDR 1/P-糖蛋白（MDR 1/P-糖蛋白）及其酸型和内酯型之间的差异，一些他汀类药物具有诱导MDR 1和/或P-糖蛋白表达的潜力。或CYP 3A以任何形式。MDR 1 mRNA表达的变化伴随着罗丹明123的CsA依赖性细胞内蓄积的变化。辛伐他汀内酯对MDR 1和CYP 3A的mRNA表达有明显的诱导作用，且呈剂量依赖性。莱菔硫烷显著抑制阿托伐他汀内酯、洛伐他汀酸和洛伐他汀内酯诱导的MDR 1和CYP 3A mRNA表达，与对照水平相当，中度抑制西立伐他汀酸、氟伐他汀酸和辛伐他汀内酯诱导的MDR 1和CYP 3A mRNA表达。在匹伐他汀酸的情况下，萝卜硫素对MDR 1 mRNA的表达没有显著影响。这些结果表明，一些他汀类药物可以诱导MDR 1和CYP 3A基因的表达，这些诱导作用之间的内酯和活性羟基酸的形式不同，PXR介导的调节很少与mRNA诱导匹伐他汀酸，不像其他他汀类药物。(C)2009爱思唯尔有限公司版权所有。
In the present study, the ability of inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR), also known as statins, to regulate the gene expression and function of multidrug resistance protein 1 (MDR1/P-glycoprotein) and differences between their acid and lactone forms were examined in human intestinal epithelial LS180 cells.Some statins had the potential to induce the expression of mRNAs for MDR1 and/or CYP3A in either form. The change in the mRNA expression of MDR1 was accompanied by a change in the CsA-dependent intracellular accumulation of rhodamine 123. Simvastatin lactone, but not the acid form, exhibited a strong inductive effect on the mRNA expression of MDR1 and CYP3A in a dose-dependent manner. Sulforaphane significantly suppressed the expression of MDR1 and CYP3A mRNAs induced by atorvastatin lactone, lovastatin acid, and lovastatin lactone, comparable to the control level, and moderately inhibited that by cerivastatin acid, fluvastatin acid and simvastatin lactone. In the case of pitavastatin acid, sulforaphane had no significant effect on the expression of MDR1 mRNA. These results suggested that some statins could induce MDR1 and CYP3A gene expression and these inductive effects differed between the lactone and active hydroxy acid forms, and that PXR-mediated regulation was rarely associated with the mRNA inducibility by pitavastatin acid, unlike that by other statins. (C) 2009 Elsevier B.V. All rights reserved.