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First published on April 19, 2005; DOI: 10.1124/mol.104.010371

0026-895X/05/6801-218-225$20.00
Mol Pharmacol 68:218-225, 2005

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Hormonal Regulation of Hepatic Organic Anion Transporting Polypeptides

M. Wood, M. Ananthanarayanan, B. Jones, R. Wooton-Kee, T. Hoffman, F. J. Suchy, and M. Vore

Graduate Center for Toxicology, University of Kentucky, Lexington, Kentucky (M.W., B.J., R.W.-K., T.H., M.V.); and Department of Pediatrics, Mount Sinai School of Medicine, New York, New York (M.A., F.J.S.)

Organic anion transporting polypeptides (Oatp) mediate the transport of a wide variety of amphipathic organic substrates. Rat Oatp1b2 and human OATP1B3 are members of a liver-specific subfamily of Oatps/OATPs. We investigated whether prolactin (PRL) and growth hormone (GH) regulated Oatp1b2 and OATP1B3 gene expression via signal transducers and activators of transcription 5 (Stat5). Binding sites for Stat5 transcription factors were located in the promoters of Oatp1b2 and OATP1B3 at –209 to –201 (5'-TTCTGGGAA-3') and –170 to –162 (5'-TTCTGAGAA-3'), respectively. In primary hepatocytes from female and male rats treated with PRL or GH, Oatp1b2 mRNA measured by real-time polymerase chain reaction was significantly induced 2-fold. HepG2 cells were transiently transfected with expression vectors containing Oatp1b2 or OATP1B3 promoter fragments, cDNAs for Stat5a, and the receptors for PRL (PRLRL) or GH (GHR), and treated with PRL or GH. PRL and GH induction of Oatp1b2 and OATP1B3 promoter activity required cotransfection of Stat5a and PRLRL or GHR. Mutation of the Stat5 binding site in both promoters eliminated hormonal induction. In DNA binding assays, HepG2 cells transfected with cDNAs for Stat5a and PRLRL were treated with PRL, and nuclear extracts were probed with a 32P-labeled oligomer corresponding to –177 to –157 of the OATP1B3 promoter. PRL enhanced the binding of Stat5a to the OATP1B3 promoter and DNA-protein binding was inhibited in competition assays by excess OATP1B3 and Stat5 consensus oligomers but not by mutant Stat5 oligomers. These findings indicate that PRL and GH can regulate Oatp1b2 and OATP1B3 gene expression via the Stat5 signal-transduction pathway.

Received December 17, 2004; accepted April 19, 2005

Address correspondence to: Dr. Mary Vore, Graduate Center for Toxicology, 306 Health Sciences Research Building, University of Kentucky, Lexington, KY 40536-0305. E-mail: maryv{at}uky.edu




This article has been cited by other articles:


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X. Cheng, J. Maher, H. Lu, and C. D. Klaassen
Endocrine Regulation of Gender-Divergent Mouse Organic Anion-Transporting Polypeptide (Oatp) Expression
Mol. Pharmacol., October 1, 2006; 70(4): 1291 - 1297.
[Abstract] [Full Text] [PDF]


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