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Originally published In Press as doi:10.1074/jbc.M202345200 on April 8, 2002

J. Biol. Chem., Vol. 277, Issue 27, 24280-24288, July 5, 2002
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Molecular Mechanisms of Polymorphic CYP3A7 Expression in Adult Human Liver and Intestine*

Oliver BurkDagger §, Heike TegudeDagger , Ina Koch, Elisabeth Hustert, Renzo WolboldDagger , Hartmut GlaeserDagger , Kathrin KleinDagger , Martin F. FrommDagger , Andreas K. Nuessler||, Peter Neuhaus||, Ulrich M. ZangerDagger , Michel EichelbaumDagger **, and Leszek WojnowskiDagger Dagger

From the Dagger  Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Auerbachstrasse 112, D-70376 Stuttgart, Germany,  Epidauros Biotechnologie AG, Am Neuland 1, D-82347 Bernried, Germany, the || Department of Surgery, Charité, Campus Virchow-Clinic, Humboldt University, D-13353 Berlin, Germany, and the ** Division of Clinical Pharmacology, Eberhard Karls University, Otfried-Müller-Strasse 10, D-72076 Tübingen, Germany

Human CYP3A enzymes play a pivotal role in the metabolism of many drugs, and the variability of their expression among individuals may have a strong impact on the efficacy of drug treatment. However, the individual contributions of the four CYP3A genes to total CYP3A activity remain unclear. To elucidate the role of CYP3A7, we have studied its expression in human liver and intestine. In both organs, expression of CYP3A7 mRNA was polymorphic. The recently identified CYP3A7*1C allele was a consistent marker of increased CYP3A7 expression both in liver and intestine, whereas the CYP3A7*1B allele was associated with increased CYP3A7 expression only in liver. Because of the replacement of part of the CYP3A7 promoter by the corresponding region of CYP3A4, the CYP3A7*1C allele contains the proximal ER6 motif of CYP3A4. The pregnane X and constitutively activated receptors were shown to bind with higher affinity to CYP3A4-ER6 than to CYP3A7-ER6 motifs and transactivated only promoter constructs containing CYP3A4-ER6. Furthermore, we identified mutations in CYP3A7*1C in addition to the ER6 motif that were necessary only for activation by the constitutively activated receptor. We conclude that the presence of the ER6 motif of CYP3A4 mediates the high expression of CYP3A7 in subjects carrying CYP3A7*1C.

* This work was supported by Deutsche Forschungsgemeinschaft Grant Bu 1249/1-1, German Federal Ministry for Education and Science Grant 01GG9846/8, and the Robert Bosch Foundation (Germany).The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

§ To whom correspondence should be addressed. Tel.: 49-711-8101-3753; Fax: 49-711-859295; E-mail: oliver.burk@ikp-stuttgart.de.

Dagger Dagger Present address: Dept. of Clinical Pharmacology, Georg August University, Robert-Koch-Str. 40, D-37075 Göttingen, Germany.

Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.
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