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First published on August 23, 2005; DOI: 10.1124/dmd.105.005249

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Received for publication April 21, 2005.
Revised August 19, 2005.
Accepted for publication August 22, 2005.

Hepatic, extrahepatic, microsomal, and mitochondrial activation of the N-hydroxylated prodrugs benzamidoxime, guanoxabenz, and Ro 48-3656

Bernd Clement 1*, Sabine Mau 1, Stephanie Deters 1, Antje Havemeyer 1

1 Christian-Albrechts-Universitat, Pharmazeutisches Institut

* Address correspondence to: E-mail: bclement{at}pharmazie.uni-kiel.de

Abstract

In previous studies it was shown that liver microsomes from rabbit, rat, pig, and human are involved in the reduction of N-hydroxylated amidines, guanidines, and amidinohydrazones of various drugs and model compounds (Clement, 2002). One responsible enzyme system, the microsomal benzamidoxime reductase, consisting of cytochrome b5, its reductase, and a P450 isoenzyme, was isolated from pig liver microsomes (Clement et al., 1997) . Further investigations followed to establish whether such enzyme systems are also present in microsomes of other organs such as brain, lung, and intestine. In addition the mitochondrial reduction in human and porcine liver and also kidney preparations were studied. The reductase activities were measured by following the reduction of benzamidoxime to benzamidine, of guanoxabenz to guanabenz, and of Ro 48-3656 to Ro 44-3888. Interestingly, preparations of all tested organs were capable of reducing the three compounds. The highest specific rates were found in kidney followed by liver, brain, lung, and intestine, and usually the mitochondrial reduction rates were superior. From the determined characteristics, similarities between the enzyme systems in the different organs and organelles were detected. Furthermore, properties of the benzamidoxime reductase located in the outer membrane of pig liver mitochondria were studied. In summary, these results demonstrate that in addition to the microsomal reduction, mitochondria are involved to a great extent in the activation of amidoxime prodrugs. The importance of extrahepatic metabolism in the reduction of N-hydroxylated prodrugs is demonstrated.


Key words: cytochrome b5, cytochrome P450, liver microsomes, microsomes, prodrugs, reductases


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A. Havemeyer, F. Bittner, S. Wollers, R. Mendel, T. Kunze, and B. Clement
Identification of the Missing Component in the Mitochondrial Benzamidoxime Prodrug-converting System as a Novel Molybdenum Enzyme
J. Biol. Chem., November 17, 2006; 281(46): 34796 - 34802.
[Abstract] [Full Text] [PDF]


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