Chisaki Ikumi, Kobayashi Masaki, Itagaki Shirou, Hirano Takeshi, Iseki Ken
Laboratory of Clinical Pharmaceutics and Therapeutics, Division of Pharmasciences, Faculty of Pharmaceutical Sciences, Hokkaido University, Kita-12-jo, Nishi-6-chome, Kita-ku, Sapporo 060-0812, Japan.
Biochim Biophys Acta. 2009 Nov;1788(11):2396-403. doi: 10.1016/j.bbamem.2009.08.014. Epub 2009 Sep 1.
Liver X receptors (LXRs) belong to the nuclear hormone receptor superfamily. Multidrug resistance-associated protein 2 (MRP2), multidrug resistance 1 (MDR1) and breast cancer resistance protein (BCRP) play an important role in the efflux of a broad range of endogenous and xenobiotic compounds from hepatocytes. Since the effects of LXR activation on there transporters have been obscure, we investigated the effects of LXR agonists, TO901317 and 25-hydroxycholesterol, on MRP2, MDR1, BCRP expression in HepG2 cells and the rat liver. In an in vitro study, TO901317 increased ABCA1, an LXR target gene, and MRP2 mRNA and protein levels. On the other hand, TO901317 had little effect on MDR1 and BCRP mRNA levels. In an in vivo study, Abca1 and Mrp2 mRNA and protein levels were increased by TO901317, but TO901317 had no effect on Mdr1a and Bcrp mRNA levels in the rat liver. Moreover, TO901317-induced MRP2 mRNA expression was blocked by LXRalpha knockdown. In this study, we demonstrated that LXR activation induced expression of MRP2 but not that of MDR1 and BCRP in hepatocytes. The results suggest that agonists for LXR activate transcription of the MRP2 gene in order to promote excretion of endogenous and xenobiotic compounds from hepatocytes into bile.
肝脏X受体（LXRs）属于核激素受体超家族。多药耐药相关蛋白2（MRP2）、多药耐药蛋白1（MDR1）和乳腺癌耐药蛋白（BCRP）在肝细胞将多种内源性和外源性化合物排出细胞的过程中发挥着重要作用。由于LXR激活对这些转运蛋白的影响尚不明确，我们研究了LXR激动剂TO901317和25-羟基胆固醇对HepG2细胞和大鼠肝脏中MRP2、MDR1、BCRP表达的影响。在体外研究中，TO901317增加了LXR靶基因ABCA1以及MRP2的mRNA和蛋白水平。另一方面，TO901317对MDR1和BCRP的mRNA水平影响不大。在体内研究中，TO901317使大鼠肝脏中Abca1和Mrp2的mRNA和蛋白水平升高，但对Mdr1a和Bcrp的mRNA水平没有影响。此外，LXRα基因敲低可阻断TO901317诱导的MRP2 mRNA表达。在本研究中，我们证明LXR激活可诱导肝细胞中MRP2的表达，但不诱导MDR1和BCRP的表达。结果表明，LXR激动剂可激活MRP2基因的转录，从而促进肝细胞将内源性和外源性化合物排泄到胆汁中。
