Table Of ContentN-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
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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
