Transport-metabolism interplay: LXRalpha-mediated induction of human ABC transporter ABCC2 (cMOAT/MRP2) in HepG2 cells.
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 LXRalpha 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 LXRalpha. The ABCC2 induction by T0901317 was more strongly elicited when the LXRalpha gene was transiently transfected into HepG2 cells. In contrast, ABCC2 induction by T0901317 was attenuated by transient transfection of a dominant negative LXRalpha variant, suggesting that LXRalpha is involved in ABCC2 induction. Interestingly, RXR, a heterodimer partner of LXRalpha, 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 LXRalpha is potentially involved in ABCC2 induction.
Adachi
Tatsuhiko
T
Department of Biomolecular Engineering, Graduate School of Bioscience and Biotechnology, Tokyo Institute of Technology, 4259-B-60 Nagatsuta-cho, Midori-ku, Yokohama 226-8501, Japan.
Nakagawa
Hiroshi
H
Hagiya
Yuichiro
Y
Yasuoka
Tatsuya
T
Ishikawa
Toshihisa
T
D000070998:ATP Binding Cassette Transporter, Subfamily G, Member 1; D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism; D000890:Anti-Infective Agents / Q000494:pharmacology; D002460:Cell Line; D045744:Cell Line, Tumor; D016572:Cyclosporine / Q000494:pharmacology; D004317:Doxorubicin / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D006845:Hydrocarbons, Fluorinated / Q000494:pharmacology; D006888:Hydroxycholesterols / Q000494:pharmacology; D015151:Immunoblotting; D007211:Indoles / Q000494:pharmacology; D000071518:Liver X Receptors; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000235:genetics / Q000378:metabolism*; D057093:Orphan Nuclear Receptors / Q000819:agonists / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering; D047490:Retinoid X Receptor alpha / Q000235:genetics / Q000502:physiology; D020123:Sirolimus / Q000494:pharmacology; D013449:Sulfonamides / Q000494:pharmacology; D005466:Fluorocarbons; D000096926:Benzenesulfonamides
D000070998:ATP Binding Cassette Transporter, Subfamily G, Member 1; D018528:ATP-Binding Cassette Transporters; D000890:Anti-Infective Agents; D016572:Cyclosporine; D004317:Doxorubicin; D006845:Hydrocarbons, Fluorinated; D006888:Hydroxycholesterols; D007211:Indoles; D000071518:Liver X Receptors; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D057093:Orphan Nuclear Receptors; D034741:RNA, Small Interfering; D047490:Retinoid X Receptor alpha; D020123:Sirolimus; D013449:Sulfonamides; C000715087:ABCC2 protein, human; C419353:ABCG1 protein, human; C000605213:NR1H3 protein, human; C423915:T0901317; D005466:Fluorocarbons; D000096926:Benzenesulfonamides; C003585:22-hydroxycholesterol; C048220:paxilline