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Xenobiotica
the fate of foreign compounds in biological systems
Volume 30, 2000 - Issue 3
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Research Article

Regioselective hydroxylation of debrisoquine by cytochrome P4502D6: implications for active site modelling

T. Lightfoot University of Sheae eld, Section of Molecular Pharmacology and Pharmacogenetics, Division of Clinical Sciences, Royal Hallamshire Hospital, Sheae eld S10 2JF, UK
,
S. W. Ellis University of Sheae eld, Section of Molecular Pharmacology and Pharmacogenetics, Division of Clinical Sciences, Royal Hallamshire Hospital, Sheae eld S10 2JF, UK
,
J. Mahling University of Sheae eld, Section of Molecular Pharmacology and Pharmacogenetics, Division of Clinical Sciences, Royal Hallamshire Hospital, Sheae eld S10 2JF, UK
,
M. J. Ackland University of Sheae eld, Section of Molecular Pharmacology and Pharmacogenetics, Division of Clinical Sciences, Royal Hallamshire Hospital, Sheae eld S10 2JF, UK
,
F. E. Blaney University of Sheae eld, Section of Molecular Pharmacology and Pharmacogenetics, Division of Clinical Sciences, Royal Hallamshire Hospital, Sheae eld S10 2JF, UK
,
G. J. Bijloo University of Sheae eld, Section of Molecular Pharmacology and Pharmacogenetics, Division of Clinical Sciences, Royal Hallamshire Hospital, Sheae eld S10 2JF, UK
,
M. J. De Groot University of Sheae eld, Section of Molecular Pharmacology and Pharmacogenetics, Division of Clinical Sciences, Royal Hallamshire Hospital, Sheae eld S10 2JF, UK
,
N. P. E. Vermeulen University of Sheae eld, Section of Molecular Pharmacology and Pharmacogenetics, Division of Clinical Sciences, Royal Hallamshire Hospital, Sheae eld S10 2JF, UK
,
G. M. Blackburn University of Sheae eld, Section of Molecular Pharmacology and Pharmacogenetics, Division of Clinical Sciences, Royal Hallamshire Hospital, Sheae eld S10 2JF, UK
,
M. S. Lennard University of Sheae eld, Section of Molecular Pharmacology and Pharmacogenetics, Division of Clinical Sciences, Royal Hallamshire Hospital, Sheae eld S10 2JF, UK
&
G. T. Tucker University of Sheae eld, Section of Molecular Pharmacology and Pharmacogenetics, Division of Clinical Sciences, Royal Hallamshire Hospital, Sheae eld S10 2JF, UK
 show all
Pages 219-233 | Published online: 22 Sep 2008

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Kevin A. Ford, Gregory Ryslik, Jasleen Sodhi, Jason Halladay, Dolo Diaz, Donna Dambach & Melisa Masuda. (2015) Computational predictions of the site of metabolism of cytochrome P450 2D6 substrates: comparative analysis, molecular docking, bioactivation and toxicological implications. Drug Metabolism Reviews 47:3, pages 291-319.
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Kevin J. Schneider & Anthony P. DeCaprio. (2013) Evaluation of in vitro metabolic systems for common drugs of abuse. 1. Cocaine. Xenobiotica 43:12, pages 1043-1054.
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Bo Wang, Li-Ping Yang, Xiao-Zhuang Zhang, Shui-Qing Huang, Mark Bartlam & Shu-Feng Zhou. (2009) New insights into the structural characteristics and functional relevance of the human cytochrome P450 2D6 enzyme. Drug Metabolism Reviews 41:4, pages 573-643.
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Andy Jennings & Mike Tennant. (2006) Discovery strategies in a pharmaceutical setting: the application of computational techniques. Expert Opinion on Drug Discovery 1:7, pages 709-721.
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N. J. Proctor, G. T. Tucker & A. Rostami-Hodjegan. (2004) Predicting drug clearance from recombinantly expressed CYPs: intersystem extrapolation factors. Xenobiotica 34:2, pages 151-178.
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Ai‐Ming Yu, Jeffrey R. Idle & Frank J. Gonzalez. (2004) Polymorphic Cytochrome P450 2D6: Humanized Mouse Model and Endogenous Substrates. Drug Metabolism Reviews 36:2, pages 243-277.
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Slobodan Rendic. (2002) Summary of information on human CYP enzymes: human P450 metabolism data. Drug Metabolism Reviews 34:1-2, pages 83-448.
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S. Ozawa, K. Ohta, A. Miyajima, H. Kurebayashi, M. Sunouchi, M. Shimizu, N. Murayama, Y. Matsumoto, M. Fukuoka & Y. Ohno. (2000) Metabolic activation of o-phenylphenol to a major cytotoxic metabolite, phenylhydroquinone: role of human CYP1A2 and rat CYP2C11/CYP2E1. Xenobiotica 30:10, pages 1005-1017.
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Articles from other publishers (27)

L. Dhers, L. Ducassou, J.-L. Boucher & D. Mansuy. (2017) Cytochrome P450 2U1, a very peculiar member of the human P450s family. Cellular and Molecular Life Sciences 74:10, pages 1859-1869.
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Lionel Ducassou, Gabriella Jonasson, Laura Dhers, Nicolas Pietrancosta, Booma Ramassamy, Yun Xu-Li, Marie-Anne Loriot, Philippe Beaune, Gildas Bertho, Murielle Lombard, Daniel Mansuy, François André & Jean-Luc Boucher. (2015) Expression in yeast, new substrates, and construction of a first 3D model of human orphan cytochrome P450 2U1: Interpretation of substrate hydroxylation regioselectivity from docking studies. Biochimica et Biophysica Acta (BBA) - General Subjects 1850:7, pages 1426-1437.
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Samuel L. C. Moors, Ann M. Vos, Maxwell D. Cummings, Herman Van Vlijmen & Arnout Ceulemans. (2011) Structure-Based Site of Metabolism Prediction for Cytochrome P450 2D6. Journal of Medicinal Chemistry 54:17, pages 6098-6105.
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Rayomand J. Unwalla, Jason B. Cross, Sumeet Salaniwal, Adam D. Shilling, Louis Leung, John Kao & Christine Humblet. (2010) Using a homology model of cytochrome P450 2D6 to predict substrate site of metabolism. Journal of Computer-Aided Molecular Design 24:3, pages 237-256.
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K. Anton Feenstra, Eugene B. Starikov, Vlada B. Urlacher, Jan N.M. Commandeur & Nico P.E. Vermeulen. (2009) Combining substrate dynamics, binding statistics, and energy barriers to rationalize regioselective hydroxylation of octane and lauric acid by CYP102A1 and mutants. Protein Science 16:3, pages 420-431.
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M.J. De Groot, D.F.V. Lewis & S. Modi. 2007. Comprehensive Medicinal Chemistry II. Comprehensive Medicinal Chemistry II 809 825 .
Graham Lappin. 2006. Radiotracers in Drug Development. Radiotracers in Drug Development 41 118 .
Paul Rowland, Frank E. Blaney, Martin G. Smyth, Jo J. Jones, Vaughan R. Leydon, Amanda K. Oxbrow, Ceri J. Lewis, Mike G. Tennant, Sandeep Modi, Drake S. Eggleston, Richard J. Chenery & Angela M. Bridges. (2006) Crystal Structure of Human Cytochrome P450 2D6. Journal of Biological Chemistry 281:11, pages 7614-7622.
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Peter H.J. Keizers, Loek H.M. Schraven, Chris de Graaf, Mats Hidestrand, Magnus Ingelman-Sundberg, Ben R. van Dijk, Nico P.E. Vermeulen & Jan N.M. Commandeur. (2005) Role of the conserved threonine 309 in mechanism of oxidation by cytochrome P450 2D6. Biochemical and Biophysical Research Communications 338:2, pages 1065-1074.
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Anja Kristina Froehlich, Ulrich Girreser & Bernd Clement. (2005) METABOLISM OF N -HYDROXYGUANIDINES ( N -HYDROXYDEBRISOQUINE) IN HUMAN AND PORCINE HEPATOCYTES: REDUCTION AND FORMATION OF GLUCURONIDES . Drug Metabolism and Disposition 33:10, pages 1532-1537.
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Delphine Allorge, Didier Bréant, Jacky Harlow, Joey Chowdry, Jean‐Marc Lo‐Guidice, Dany Chevalier, Christelle Cauffiez, Michel Lhermitte, Frank E. Blaney, Geoffrey T. Tucker, Franck Broly & S. Wynne Ellis. (2005) Functional analysis of CYP2D6.31 variant: Homology modeling suggests possible disruption of redox partner interaction by Arg440His substitution. Proteins: Structure, Function, and Bioinformatics 59:2, pages 339-346.
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Chris de Graaf, Nico P. E. Vermeulen & K. Anton Feenstra. (2005) Cytochrome P450 in Silico:  An Integrative Modeling Approach. Journal of Medicinal Chemistry 48:8, pages 2725-2755.
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F. Peter Guengerich. 2005. Cytochrome P450. Cytochrome P450 377 530 .
Martin Payne. 2004. Predicting Chemical Toxicity and Fate. Predicting Chemical Toxicity and Fate.
M. R. Shiran, J. Chowdry, A. Rostami‐Hodjegan, S. W. Ellis, M. S. Lennard, M. Z. Iqbal, O. Lagundoye, N. Seivewright & G. T. Tucker. (2003) A discordance between cytochrome P450 2D6 genotype and phenotype in patients undergoing methadone maintenance treatment. British Journal of Clinical Pharmacology 56:2, pages 220-224.
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Suresh B. Singh, Lucy Q. Shen, Matthew J. Walker & Robert P. Sheridan. (2003) A Model for Predicting Likely Sites of CYP3A4-mediated Metabolism on Drug-like Molecules. Journal of Medicinal Chemistry 46:8, pages 1330-1336.
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Jennifer Venhorst, Antonius M. ter Laak, Jan N. M. Commandeur, Yoshihiko Funae, Toyoko Hiroi & Nico P. E. Vermeulen. (2002) Homology Modeling of Rat and Human Cytochrome P450 2D (CYP2D) Isoforms and Computational Rationalization of Experimental Ligand-Binding Specificities. Journal of Medicinal Chemistry 46:1, pages 74-86.
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N. P. E. Vermeulen. 2003. Stereochemical Aspects of Drug Action and Disposition. Stereochemical Aspects of Drug Action and Disposition 229 248 .
Tashinga E Bapiro, Julia A Hasler, Marianne Ridderström & Collen M Masimirembwa. (2002) The molecular and enzyme kinetic basis for the diminished activity of the cytochrome P450 2D6.17 (CYP2D6.17) variant. Biochemical Pharmacology 64:9, pages 1387-1398.
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Marcel J. de Groot & Sean Ekins. (2002) Pharmacophore modeling of cytochromes P450. Advanced Drug Delivery Reviews 54:3, pages 367-383.
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Jeffrey P. Jones, Michael Mysinger & Kenneth Ray Korzekwa. (2002) Computational Models for Cytochrome P450: A Predictive Electronic Model for Aromatic Oxidation and Hydrogen Atom Abstraction. Drug Metabolism and Disposition 30:1, pages 7-12.
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Delphine Allorge, Jacky Harlow, Olivier Boulet, Graham P. Hayhurst, Joey Chowdry, Emma Roth, Kim Crewe, Jean-Marc Lo-Guidice, Michel Lhermitte, Franck Broly, Geoffrey T. Tucker & S. Wynne Ellis. (2001) In-vitro analysis of the contribution of CYP2D6.35 to ultra-rapid metabolism. Pharmacogenetics 11:8, pages 739-741.
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Imad H. Hanna, Joel A. Krauser, Hongliang Cai, Mi-Sook Kim & F. Peter Guengerich. (2001) Diversity in Mechanisms of Substrate Oxidation by Cytochrome P450 2D6. Journal of Biological Chemistry 276:43, pages 39553-39561.
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David Lewis. 2001. Guide to Cytochromes P450. Guide to Cytochromes P450 164 210 .
Gordon Dear, Robert Plumb & Dave Mallett. (2000) Use of monolithic silica columns to increase analytical throughput for metabolite identification by liquid chromatography/tandem mass spectrometry. Rapid Communications in Mass Spectrometry 15:2, pages 152-158.
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David J.M Spalding, Andrew J Harker & Martin K Bayliss. (2000) Combining high-throughput pharmacokinetic screens at the hits-to-leads stage of drug discovery. Drug Discovery Today 5:12, pages 70-76.
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David J.M. Spalding, Andrew J. Harker & Martin K. Bayliss. (2000) Combining high-throughput pharmacokinetic screens at the hits-to-leads stage of drug discovery. Drug Discovery Today 5, pages S70-S76.
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