HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) Submit a Letter to Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Clement, B. Articles by Möller, W. Search for Related Content PubMed PubMed Citation Articles by Clement, B. Articles by Möller, W. Social Bookmarking                      What's this?

Volume 272, Number 31, Issue of August 1, 1997 pp. 19615-19620
©1997 by The American Society for Biochemistry and Molecular Biology, Inc.

Isolation and Characterization of the Protein Components of the Liver Microsomal O₂-insensitive NADH-Benzamidoxime Reductase

(Received for publication, September 27, 1996, and in revised form, May 27, 1997)

From the Pharmazeutisches Institut, Christian-Albrechts-Universität zu Kiel, Gutenbergstr. 76, 24118 Kiel, Germany

Drugs containing strong basic nitrogen functional groups can be N-oxygenated to genotoxic products. While the reduction of such products is of considerable toxicological significance, most in vitro studies have focused on oxygen-sensitive reductase systems. However, an oxygen-insensitive microsomal hydroxylamine reductase consisting of NADH, cytochrome b₅, its reductase, and a third unidentified protein component has been known for some time (Kadlubar, F. F., and Ziegler, D. M. (1974) Arch. Biochem. Biophys. 162, 83-92). This report describes the isolation and identification of all of the components required for the reconstitution of an oxygen-insensitive liver microsomal system capable of catalyzing the efficient reduction of primary N-hydroxylated structures such as amidines, guanidines, amidinohydrazones, and similar functional groups. In addition to cytochrome b₅ and its reductase, the reconstituted system requires phosphatidylcholine and a P450 isoenzyme that has been purified to homogeneity from pig liver. The participation of cytochrome b₅ and NADH cytochrome b₅ reductase in cytochrome P450-dependent biotransformations has previously only been described for oxidative processes. The data presented suggest that this system may be an important catalyst in the reduction of genotoxic N-hydroxylated nitrogen components in liver. Their facile reduction by cellular NADH may be the reason why N-hydroxylated products can be missed by studies in vivo. Furthermore, the enzyme system is involved in the reduction of amidoximes and similar functional groups, which can be used as prodrug functionalities for amidines and related groups.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

				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]

				J. Y. Saulter, J. R. Kurian, L. A. Trepanier, R. R. Tidwell, A. S. Bridges, D. W. Boykin, C. E. Stephens, M. Anbazhagan, and J. E. Hall UNUSUAL DEHYDROXYLATION OF ANTIMICROBIAL AMIDOXIME PRODRUGS BY CYTOCHROME b5 AND NADH CYTOCHROME b5 REDUCTASE Drug Metab. Dispos., December 1, 2005; 33(12): 1886 - 1893. [Abstract] [Full Text] [PDF]

				B. Clement, S. Mau, S. Deters, and A. Havemeyer Drug Metab. Dispos., November 1, 2005; 33(11): 1740 - 1747. [Abstract] [Full Text] [PDF]

				S. Andersson, Y. Hofmann, A. Nordling, X.-q. Li, S. Nivelius, T. B. Andersson, M. Ingelman-Sundberg, and I. Johansson CHARACTERIZATION AND PARTIAL PURIFICATION OF THE RAT AND HUMAN ENZYME SYSTEMS ACTIVE IN THE REDUCTION OF N-HYDROXYMELAGATRAN AND BENZAMIDOXIME Drug Metab. Dispos., April 1, 2005; 33(4): 570 - 578. [Abstract] [Full Text] [PDF]

				J. R. Kurian, S. U. Bajad, J. L. Miller, N. A. Chin, and L. A. Trepanier NADH Cytochrome b5 Reductase and Cytochrome b5 Catalyze the Microsomal Reduction of Xenobiotic Hydroxylamines and Amidoximes in Humans J. Pharmacol. Exp. Ther., December 1, 2004; 311(3): 1171 - 1178. [Abstract] [Full Text] [PDF]

				B. Clement and K. Lopian Characterization of in Vitro Biotransformation of New, Orally Active, Direct Thrombin Inhibitor Ximelagatran, an Amidoxime and Ester Prodrug Drug Metab. Dispos., May 1, 2003; 31(5): 645 - 651. [Abstract] [Full Text] [PDF]

				P. Anzenbacher, E. Anzenbacherova, R. Zuber, P. Soucek, F. P. Guengerich, M. J. Myers, D. E. Farrell, K. D. Howard, and J. C. Kawalek Pig and Minipig Cytochromes P450 Drug Metab. Dispos., January 1, 2002; 30(1): 100 - 102. [Full Text] [PDF]

				S. Kitamura, K. Sugihara, and K. Tatsumi A Unique Tertiary Amine N-Oxide Reduction System Composed of Quinone Reductase and Heme in Rat Liver Preparations Drug Metab. Dispos., January 1, 1999; 27(1): 92 - 97. [Abstract] [Full Text]

				B. Clement and M. Demesmaeker Formation of Guanoxabenz from Guanabenz in Human Liver. A new metabolic marker for CYP1A2 Drug Metab. Dispos., November 1, 1997; 25(11): 1266 - 1271. [Abstract] [Full Text]