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First published on December 21, 2007; DOI: 10.1124/mol.107.043869

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Received for publication November 27, 2007.
Revised December 21, 2007.
Accepted for publication December 21, 2007.

Midazolam metabolism in Cytochrome P450 3A knockout mice can be attributed to upregulated CYP2C enzymes

Robert A.B. van Waterschoot 1, Antonius E. van Herwaarden 1, Jurjen S. Lagas 1, Rolf W. Sparidans 2, Els Wagenaar 1, Cornelia M.M. van der Kruijssen 1, Joyce A. Goldstein 3, Darryl C. Zeldin 4, Jos H. Beijnen 5, Alfred H. Schinkel 1*

1 Division of Experimental Therapy, The Netherlands Cancer Institute, Amsterdam, The Netherlands 2 Department of Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands 3 Laboratory of Pharmacology and Chemistry, NIEHS, NIH 4 Laboratory of Respiratory Biology, NIEHS, NIH 5 Slotervaart Hospital, Department of Pharmacy and Pharmacology, Amsterdam, The Netherlands

* Address correspondence to: E-mail: a.schinkel{at}nki.nl

Abstract

The cytochrome P450 3A (CYP3A) enzymes represent one of the most important drug-metabolizing systems in human. Recently, our group has generated cytochrome P450 3A knockout mice to study this drug-handling system in vivo. Here, we have characterized the Cyp3a knockout mice by studying the metabolism of midazolam, one of the most widely used probes to assess CYP3A activity. We expected that the midazolam metabolism would be severely reduced in the absence of CYP3A enzymes. We used hepatic and intestinal microsomal preparations from Cyp3a knockout and wild-type mice to assess the midazolam metabolism in vitro. In addition, in vivo metabolite formation was determined after intravenous administration of midazolam. Surprisingly, our results demonstrated that there is still marked midazolam metabolism in hepatic (but not intestinal) microsomes from Cyp3a knockout mice. Accordingly, we found comparable amounts of midazolam as well as its major metabolites in plasma after intravenous administration in Cyp3a knockout mice when compared to wild-type mice. These data suggested that other hepatic cytochrome P450 enzymes could take over the midazolam metabolism in Cyp3a knockout mice. We provide evidence that CYP2C enzymes, which were found to be upregulated in Cyp3a knockout mice, are primarily responsible for this metabolism and that several but not all murine CYP2C enzymes are capable of metabolizing midazolam to its 1'-OH and/or 4-OH derivatives. These data illustrate interesting compensatory changes that may occur in Cyp3a knockout mice. Such flexible compensatory interplay between functionally related detoxifying systems is probably essential to their biological role in xenobiotic protection.


Key words: Cytochrome P450, Regulation - transcriptional, Regulation - xenobiotic


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