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Originally published In Press as doi:10.1074/jbc.M314111200 on March 5, 2004

J. Biol. Chem., Vol. 279, Issue 21, 22250-22257, May 21, 2004
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Interactions between Hepatic Mrp4 and Sult2a as Revealed by the Constitutive Androstane Receptor and Mrp4 Knockout Mice*

Mahfoud Assem{ddagger}, Erin G. Schuetz{ddagger}, Markos Leggas{ddagger}, Daxi Sun{ddagger}, Kazuto Yasuda{ddagger}, Glen Reid§, Noam Zelcer§, Masashi Adachi{ddagger}, Stephen Strom¶, Ronald M. Evans||, David D. Moore**, Piet Borst§, and John D. Schuetz{ddagger}{ddagger}{ddagger}

From the {ddagger}Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, the §Division of Molecular Biology and Center for Biomedical Genetics, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands, the **Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas 77030, the ||Gene Expression Laboratory, Howard Hughes Medical Institute, The Salk Institute for Biological Studies, La Jolla, California 92037, and the Department of Pathology, University of Pittsburgh, Pittsburgh, Pennsylvania 15261

The ABC transporter, Mrp4, transports the sulfated steroid DHEA-s, and sulfated bile acids interact with Mrp4 with high affinity. Hepatic Mrp4 levels are low, but increase under cholestatic conditions. We therefore inferred that up-regulation of Mrp4 during cholestasis is a compensatory mechanism to protect the liver from accumulation of hydrophobic bile acids. We determined that the nuclear receptor CAR is required to coordinately up-regulate hepatic expression of Mrp4 and an enzyme known to sulfate hydroxy-bile acids and steroids, Sult2a1. CAR activators increased Mrp4 and Sult2a1 expression in primary human hepatocytes and HepG2, a human liver cell line. Sult2a1 was down-regulated in Mrp4-null mice, further indicating an inter-relation between Mrp4 and Sult2a1 gene expression. Based on the hydrophilic nature of sulfated bile acids and the Mrp4 capability to transport sulfated steroids, our findings suggest that Mrp4 and Sult2a1 participate in an integrated pathway mediating elimination of sulfated steroid and bile acid metabolites from the liver.

Received for publication, December 23, 2003 , and in revised form, March 3, 2004.

* This work was supported by National Institutes of Health Research Grants CA77545, GM60904, ES058571, GM60346, U01-GM61393, P30 CA21745, a Cancer Center support grant, the American Lebanese Syrian Associated Charities (ALSAC), and Dutch Cancer Society Grants NKI 2001-2473 and NKI 1998-1764. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

{ddagger}{ddagger} To whom correspondence should be addressed: Dept. of Pharmaceutical Sciences, St. Jude Children's Research Hospital, 332 N. Lauderdale Ave., Memphis, TN 38105-2794. Tel.: 901-495-2174; Fax: 901-525-6869; E-mail: John.schuetz{at}stjude.org.


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