Transport−Metabolism Interplay: LXRα-Mediated Induction of Human ABC Transporter ABCC2 (cMOAT/MRP2) in HepG2 Cells
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- 作者：Tatsuhiko Adachi ; Hiroshi Nakagawa ; Yuichiro Hagiya ; Tatsuya Yasuoka ; Toshihisa Ishikawa
- 刊名：Molecular Pharmaceutics
- 出版年：2009
- 出版时间：December 7, 2009
- 年：2009
- 卷：6
- 期：6
- 页码：1678-1688
- 全文大小：278K
- 年卷期：v.6,no.6(December 7, 2009)
- ISSN：1543-8392
文摘
Human ATP-binding cassette (ABC) transporter ABCC2 (cMOAT/MRP2) plays a crucial role in the hepatobiliary transport of sulfate-, glucuronide-, and glutathione-conjugated metabolites as well as a variety of amphiphilic organic anions derived from hepatic metabolism. Molecular mechanisms underlying the induction of this hepatic ABC transporter are of great interest to understand the transport−metabolism interplay in vivo. In the present study, to gain insight into the mechanism of ABCC2 induction, we tested a total of 46 structurally diverse compounds, including nuclear receptor ligands, antibiotics, bile salts, phytochemicals, and anticancer drugs. Among them, we found that LXRα ligands, i.e., T0901317, paxilline, and 22(R)-hydroxycholesterol, acted potently to induce the expression of ABCC2 at both mRNA and protein levels in human hepatocellular carcinoma HepG2 cells. The ABCC2 induction by T0901317 was dose- and time-dependent, where the induction pattern of ABCC2 was very similar to that of ABCG1, one of the target genes of LXRα. The ABCC2 induction by T0901317 was more strongly elicited when the LXRα gene was transiently transfected into HepG2 cells. In contrast, ABCC2 induction by T0901317 was attenuated by transient transfection of a dominant negative LXRα variant, suggesting that LXRα is involved in ABCC2 induction. Interestingly, RXR, a heterodimer partner of LXRα, affected the mRNA levels of ABCC2 and ABCG1 differently. ABCC2 induction by T0901317 was enhanced by RXR siRNA treatment, whereas ABCG1 induction was suppressed by the same treatment. This is the first report demonstrating that LXRα is potentially involved in ABCC2 induction.