Table Of Content

N-Oxidation ofDrugs This volume is dedicated to Professor Dan Ziegler in recognition of his extensivecontributionsto theenzymologyofN-oxidation. N-Qxidation of Drugs Biochemistry, pharmacology, toxicology Edited by P. Hlavica Full Professor of Pharmacology and Toxicology, Ludwig-Maximilians-Universitiit Munchen, Munich, Germany L.A. Damani Lecturer in Biopharmacy, King's College, London, UK Ig!11 SPRINGER-SCIENCE+BUSINESS MEDIA, B.V. First edition 1991 © 1991 Springer Science+Business Media Dordrecht Originally published by Chapman & Hali in 1991 Softcover reprint ofthe hardcover Ist edition 1991 Typeset in 1O/12pt Times by EJS Chemical Composition, Midsomer Norton, Bath, Avon Bury St Edmunds, Suffolk ISBN 978-94-010-5378-5 Apart from any fair dealing for the purposes of research or private study, or criticism or review, as permitted under the UK Copyright Designs and Patents Act, 1988, this publication may not be reproduced, stored, or transmitted, in any form or by any means, without the prior permission in writing of the publishers, or in the case of reprographic reproduction only in accordance with the terms of the licences issued by the Copyright Licensing Agency in the UK, or in accordance with the terms of licences issued by the appropriate Reproduction Rights Organizat ion outside the UK. Enquiries concerning reproduction outside the terms stated here should be sent to the publishers at the UK address printed on this page. The publisher makes no representation, express or implied, with regard to the accuracy of the information contained in this book and cannot accept any legal responsibility or liability for any errors or omissions that may be made. British Library Cataloguing in Publication Data N-oxidation of drugs: Biochemistry, pharmacology, toxicology. 1. Hlavica, P. II. Damani, L.A. 615 ISBN 978-94-010-5378-5 ISBN 978-94-011-3112-4 (eBook) DOI 10.1007/978-94-011-3112-4 Library of Congress Cataloging-in-Publication Data Available Contents Contributors XIlI Preface XIX PART ONE ANALYSIS OF N-OXIDIZED PRODUCTS 1 Formationofaromaticaminefreeradicalsby prostaglandin hydroperoxidaseandperoxylradicals: analysisbyESRand stableend products 3 T.E. Eling, IF. Curtis, D.C. Thompson, J. van der Zee andR.P. Mason 1.1 Introduction 4 1.2 Metabolismofaromaticamines 6 1.3 Mechanism for the N-dealkylationofN-substituted amines 8 1.4 A new mechanismfor the oxidationofamines 14 1.5 Conclusions 17 References 17 2 TheapplicationofISN_NMRintheanalysisofN-oxygenated amidinesandguanidines 19 B. Clementand Th. Kiimpchen 2.1 Introduction 20 2.2 Technical aspectsofmeasuring 15N_NMRspectra 21 2.3 AnalysisofvariousclassesofN-oxidizedcompounds 23 2.4 Conclusions 34 References 34 3 Radioimmunoassayandothermethodsfor traceanalysisof N-oxidecompounds 37 K.K. Midha, T.J. Jaworski, E.M. Hawes, G. McKay, J.W. Hubbard, M. AravagiriandS.R. Marder 3.1 Introduction 38 3.2 Definingthe problem 39 VI Contents 3.3 Techniquesavailablefor thequalitative andquantitative analysisofintact N-oxides 43 3.4 Conclusions 53 References 54 PART TWO ENZYMOLOGY OF N-OXIDATION 4 Mechanism, multipleformsandsubstratespecificitiesofflavin- containingmono-oxygenases 59 D.M. Ziegler 4.1 Introduction 60 4.2 Multipleforms 60 4.3 Mechanism 62 4.4 Specificity 65 4.5 Inhibitors 66 References 68 5 Onthegeneticpolymorphismoftheflavin-containing mono- oxygenase 71 P. Hlavica andI. Golly 5.1 Introduction 72 5.2 Factorsprovidingindirectevidence oftheexistenceof multipleFMO forms 72 5.3 Factorsprovidingdirectevidenceoftheexistenceof multiple FMOforms 79 5.4 Conclusions 86 References 86 6 Factorsregulatingtheactivityoftherabbitlungflavin- containingmono-oxygenase 91 D.E. Williams 6.1 Introduction 92 6.2 Purificationand distinct propertiesofrabbit lungFMO 93 6.3 Regulation ofmaternal andfetal rabbit lungFMOduring pregnancy 95 6.4 Diurnal regulationofrabbit FMO 95 6.5 Phospholipidbindingto lungFMO and modulation ofactivity 99 6.6 InhibitionofFMObytannicacid 102 6.7 Conclusions 102 References 103 Contents Vll 7 Human pharmacogeneticsofnitrogenoxidations 107 S. Cholerton andR.L. Smith 7.1 Introduction 108 7.2 Human pharmacogenetics 108 7.3 Nitrogenoxidations 110 7.4 Primarytrimethylaminuria: a pharmacogeneticphenomenon ofnitrogenoxidation 111 7.5 Secondarytrimethylaminurias: the consequenceofreduced N-oxidationcapacity 122 7.6 ImplicationsofreducedN-oxidation capacityonthe metabolismofotherxenobiotics 125 References 127 8 MicrobialN-hydroxylases 133 H. DiekmannandH.J. Plattner 8.1 Introduction 134 8.2 StudiesonAerobacteraerogenes62-1 134 8.3 Studieson aerobactin biosynthesisencodedon peolV plasmids 135 8.4 Studieswith Gram-positive bacteria 136 8.5 Studiesonfungi 136 References 137 9 Rolesofaminium radicalintermediatesin the biotransformation ofdihydropyridines,cycloalkylamines,and N,N-dimethylanilines bycytochromeP-450enzymes 141 F.P. Guengerich, A. Bondon, R.G. Boekerand T.L. Macdonald 9.1 Introduction 142 9.2 FormationofN-Ocompounds 143 9.3 Ringexpansionofacyclobutylamine 147 9.4 Oxidationofdihydropyridines 148 9.5 Estimation oftheoxidation potentialofthe active oxygenatingspeciesofP-450 151 References 152 10 TheroleofcytochromeP-450in thebiologicalnuclear N-oxidationofaminoazaheterocyclicdrugsandrelated compounds 157 J.W. GorrodandS.P. Lam 10.1 Introduction 158 10.2 Observationsofmetabolic N-oxidationofaminoazahetero- cycles 162 viii Contents 10.3 EnzymologyofnuclearN-oxidationofaminoazahetero- cycles 164 10.4 Factorsinvolvedin the N-oxidationofaminoazahetero- cycles 168 10.5 Substrate-enzymecomplexformation 176 10.6 Conclusions 181 References 181 11 NewaspectsofthemicrosomalN-hydroxylationofbenzamidines 185 B. Clement, M. Immel, H. Pfundner, S. Schmittand M. Zimmermann 11.1 Introduction 186 11.2 Aspectsofmetabolicinvestigationswithamidines 187 11.3 Microsomal N-hydroxylationofN,N-unsubstituted benzamidines 188 11.4 Structure-activityrelationshipsand mechanismsofthe N-oxidative metabolismofamidines 191 11.5 PredictabilityofN-oxygenations bycytochrome P-450 derivedfrom studieson amidines 198 11.6 Furthertransformationsofbenzamidoxime and benzamidine 200 11.7 PharmacologicalpropertiesofN-oxygenated metabolites 203 11.8 Genotoxicactivitiesofbenzamidoxime 203 References 204 12 StudiesontheN-oxidationofphentermine:evidencefor an indirectpathwayofN-oxidation mediated bycytochromeP-450 207 A.K. Cho, J.D. DuncanandJ.M. Fukuto 12.1 Introduction 208 12.2 Biochemicalstudieswith microsomes 209 12.3 Biochemicalstudieswith reconstitutedsystems 210 12.4 Superoxide-mediated reactions: possiblemechanisms 212 12.5 Conclusions 214 References 215 13 Molecularactivationmechanismsinvolvedinarylamine cytotoxicity: peroxidaseproducts 217 P.l.O'Brien, S. Jatoe, L.G. McGirrandS. Khan 13.1 Introduction 218 13.2 Enzymicmechanismsofacetaminophen bioactivation and cytotoxicity 218 13.3 Bioactivationofacetaminophen and aminophenol in hepatocytesin the presenceofhalides 224 Contents ix 13.4 Conclusions 229 References 233 PART THREE REDUCTIONS AND CONJUGATIONS OF N-OXYGENATED COMPOUNDS 14 ReductionandconjugationreactionsofN-oxides 239 L.A. Damani 14.1 Introduction 240 14.2 FurthertransformationsofN-oxides 241 14.3 Conclusions 255 References 258 15 In vivometabolismofN-oxides 263 E.M. Hawes, T.J. Jaworski, K.K. Midha, G. McKay, J.W. HubbardandE.D. Korchinski 15.1 Introduction 264 15.2 In vivo metabolismoftricyclicantidepressantN-oxides 265 15.3 In vivo metabolismofchlorpromazineN-oxide 270 15.4 Comparisonofstudiesinvolvingamitriptyline N-oxide and chlorpromazine N-oxide 281 15.5 Conclusions 283 References 283 16 Purificationand characterizationofrathepaticacetyltransferase 287 C.M. KingandS.J. Land 16.1 Introduction 288 16.2 Enzymesresponsible for formation ofreactive N-acetoxyarylamine metabolites 289 16.3 Conclusion 291 References 291 PART FOUR BIOACTIVATION OF NITROGENOUS COMPOUNDS AND CELL TOXICITY 17 Metabolismandactivationofnitrosaminescatalysed bycytochrome P-450isoenzymes 295 C.S. Yang, T. Smith, H. Ishizaki, 1.S.H. Yoo andJ.-Y. Hong 17.1 Introduction 296 17.2 EnzymologyofNDMA metabolism 296 17.3 Kineticsand mechanismsofNDMA metabolism 298 17.4 The role ofcytochrome P450IIEI in the activation ofNDMA 299 17.5 Regulationandfunctions ofcytochromeP450IIEI 301 x Contents 17.6 Substratespecificityand alkylgroupselectivityin the metabolismofothernitrosamines 303 17.7 Metabolismof4-(N-nitrosomethylamino)-1-(3-pyridyl)- 1-butanone(NHK) 304 17.8 Organspecificityin nitrosamine metabolismand carcinogenesis 307 References 308 18 CytochromeP-450-catalysedactivationofcarcinogenicaromatic aminesandamides 313 P.D. Lotlikar 18.1 Introduction 314 18.2 AAFN-hydroxylation bylivermicrosomes 315 18.3 N-Hydroxylationofvariousaromaticamides 316 18.4 N-Oxidation ofaromaticamines 317 18.5 Kineticstudieswith microsomal preparations 320 18.6 Resolution and reconstitution ofthe cytochrome P-450 enzymesystem 323 18.7 Conclusions 325 References 325 19 ComparativebiochemistryofcytochromeP-450speciesresponsible for theactivationofmutagenicfood-derived heterocyclicamines 331 T. Kamataki, M. Kitada, M. Komori, K. Ohta, T. Uchida, O. Kikuchi, M. Taneda and H. Fukuta 19.1 Introduction 332 19.2 Activation ofmutagenicfood-derived heterocyclicamines by liver microsomes 333 19.3 Activationofmutagenic heterocyclicaminesbyhumanfetal livercytochrome P-450 333 19.4 Purification and propertiesofP-450-D2and P-450-D3from liver microsomesofPCB (KC-500)-treateddogs 335 19.5 Molecularcloningandexpression ofdog livercytochrome P-450 338 19.6 Molecularcloningandexpression ofmonkeyliver cytochrome P-450 340 19.7 Conclusions 341 References 342 20 Specificityand inducibilityofcytochromeP-450catalysingthe activationoffood-derived mutagenic heterocyclicamines 345 A.R. Boobis, D. Sesardic, B.P. Murray, R.J. Edwards and D. S. Davies 20.1 Introduction 346