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J. Biol. Chem., Vol. 279, Issue 12, 11336-11343, March 19, 2004

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Feed-forward Regulation of Bile Acid Detoxification by CYP3A4

STUDIES IN HUMANIZED TRANSGENIC MICE^*

Catherine Stedman, Graham Robertson¶, Sally Coulter, and Christopher Liddle||**

From the Departments of Clinical Pharmacology and ^¶Medicine, University of Sydney, Molecular Pharmacology Laboratory and Storr Liver Unit, Westmead Millennium Institute and ^||Institute of Clinical Pathology and Medical Research, Westmead Hospital, New South Wales 2145, Australia

Bile acids are potentially toxic end products of cholesterol metabolism and their concentrations must be tightly regulated. Homeostasis is maintained by both feed-forward regulation and feedback regulation. We used humanized transgenic mice incorporating 13 kb of the 5' regulatory flanking sequence of CYP3A4 linked to a lacZ reporter gene to explore the in vivo relationship between bile acids and physiological adaptive CYP3A gene regulation in acute cholestasis after bile duct ligation (BDL). Male transgenic mice were subjected to BDL or sham surgery prior to sacrifice on days 3, 6, and 10, and others were injected with intraperitoneal lithocholic acid (LCA) or vehicle alone. BDL resulted in marked hepatic activation of the CYP3A4/lacZ transgene in pericentral hepatocytes, with an 80-fold increase in transgene activation by day 10. Individual bile acids were quantified by liquid chromatography/mass spectrometry. Serum 6-hydroxylated bile acids were increased following BDL, confirming the physiological relevance of endogenous Cyp3a induction to bile acid detoxification. Although concentrations of conjugated primary bile acids increased after BDL, there was no increase in LCA, a putative PXR ligand, indicating that this cannot be the only endogenous bile acid mediating this protective response. Moreover, in LCA-treated animals, 5-bromo-4-chloro-3-indolyl--D-galactopyranoside staining showed hepatic activation of the CYP3A4 transgene only on the liver capsular surface, and minimal parenchymal induction, despite significant liver injury. This study demonstrates that CYP3A up-regulation is a significant in vivo adaptive response to cholestasis. However, this up-regulation is not dependent on increases in circulating LCA and the role of other bile acids as regulatory molecules requires further exploration.

Received for publication, September 16, 2003 , and in revised form, December 17, 2003.

^* This work was supported in part by project grants from the National Health and Medical Research Council of Australia. 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.

Recipient of financial support from the Clinical Hepatology Trust Fund Westmead Hospital, a Westmead Millennium Foundation Initiating Grant, New Zealand Gastroenterology Society/Ferring Pharmaceuticals Research Fellowship, and a National Health and Medical Research Council of Australia Postgraduate Medical Research Scholarship.

^** To whom correspondence should be addressed: Dept. of Clinical Pharmacology, Westmead Hospital, Darcy Rd., Westmead, New South Wales 2145, Australia. Tel.: 61-2-9845-6086; Fax: 61-2-9845-8351; E-mail: chris_liddle{at}wmi.usyd.edu.au.

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