N-Oxidation of Drugs: Biochemistry, pharmacology, toxicology by P. HlavicaN-Oxidation of Drugs: Biochemistry, pharmacology, toxicology by P. Hlavica

N-Oxidation of Drugs: Biochemistry, pharmacology, toxicology

byP. Hlavica, L.A. Damani

Paperback | September 24, 2012

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The metabolic N-oxidation ofnitrogenousxenobiotics has been reported tc occur in many biologicalsystems, in addition to mammaliantissues, and the mechanisms appear to differ in many respects from those involved in oxidative attack atcarbon centres. Theextensive useofnitrogen-containing compounds as pharmaceuticals and chemical intermediates can lead to exposure to alarge numberofthese agentsunderwidelyvaryingconditions. Biotransformation of these xenobiotics by N-oxidative pathways can effect detoxication, butequallywellcaninduceformation ofcytotoxicmetabolites or potential promutagens and procarcinogens. The substantial progress, in recent years, in our understanding ofthe biochemistry and toxicology of N­ oxidation of nitrogenous structures has created a need for a synthesis of current knowledge. This book provides a wide-ranging review of the state-of-the-art in nitrogen xenobiochemistry divided into four parts. The introductory chapter discusses recent developments in trace analysis of radical intermediates and other N-oxygenated products by physical and immunochemical techniques. Special attention is given in Part Two to the enzymology of N-oxidation. Thus, detailed account is given of the mechanism and substrate specificity of the flavin-containing mono­ oxygenase and factors regulating its activity are addressed. A separate chapter outlines the polymorphic expression of flavoprotein-dependent reactions. Similarly, the mechanistic background and inducibility of cytochrome P-450-catalysed turnover of specific types of nitrogenous compounds is highlighted. Data are also compiled describing the role of peroxidative N-oxidation of xenobiotics in extrahepatic tissues lacking significant amounts ofcytochrome P-450.
Title:N-Oxidation of Drugs: Biochemistry, pharmacology, toxicologyFormat:PaperbackDimensions:487 pages, 23.5 × 15.5 × 0.02 inPublished:September 24, 2012Publisher:Springer-Verlag/Sci-Tech/TradeLanguage:English

The following ISBNs are associated with this title:

ISBN - 10:9401053782

ISBN - 13:9789401053785

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Table of Contents

One Analysis of N-Oxidized Products.- 1 Formation of aromatic amine free radicals by prostaglandin hydroperoxidase and peroxyl radicals: analysis by ESR and stable end products.- 1.1 Introduction.- 1.2 Metabolism of aromatic amines.- 1.3 Mechanism for the N-dealkylation of N-substituted amines.- 1.4 A new mechanism for the oxidation of amines.- 1.5 Conclusions.- References.- 2 The application of 15N-NMR in the analysis of N-oxygenated amidines and guanidines.- 2.1 Introduction.- 2.2 Technical aspects of measuring 15N-NMR spectra.- 2.3 Analysis of various classes of N-oxidized compounds.- 2.4 Conclusions.- References.- 3 Radioimmunoassay and other methods for trace analysis of N-oxide compounds.- 3.1 Introduction.- 3.2 Defining the problem.- 3.3 Techniques available for the qualitative and quantitative analysis of intact N-oxides.- 3.4 Conclusions.- References.- Two Enzymology of N-Oxidation.- 4 Mechanism, multiple forms and substrate specificities of flavincontaining mono-oxygenases.- 4.1 Introduction.- 4.2 Multiple forms.- 4.3 Mechanism.- 4.4 Specificity.- 4.5 Inhibitors.- References.- 5 On the genetic polymorphism of the flavin-containing monooxygenase.- 5.1 Introduction.- 5.2 Factors providing indirect evidence of the existence of multiple FMO forms.- 5.3 Factors providing direct evidence of the existence of multiple FMO forms.- 5.4 Conclusions.- References.- 6 Factors regulating the activity of the rabbit lung flavincontaining mono-oxygenase.- 6.1 Introduction.- 6.2 Purification and distinct properties of rabbit lung FMO.- 6.3 Regulation of maternal and fetal rabbit lung FMO during pregnancy.- 6.4 Diurnal regulation of rabbit FMO.- 6.5 Phospholipid binding to lung FMO and modulation of activity.- 6.6 Inhibition of FMO by tannic acid.- 6.7 Conclusions.- References.- 7 Human pharmacogenetics of nitrogen oxidations.- 7.1 Introduction.- 7.2 Human pharmacogenetics.- 7.3 Nitrogen oxidations.- 7.4 Primary trimethylaminuria: a pharmacogenetic phenomenon of nitrogen oxidation.- 7.5 Secondary trimethylaminurias: the consequence of reduced N-oxidation capacity.- 7.6 Implications of reduced N-oxidation capacity on the metabolism of other xenobiotics.- References.- 8 Microbial N-hydroxylases.- 8.1 Introduction.- 8.2 Studies on Aerobacter aerogenes 62-1.- 8.3 Studies on aerobactin biosynthesis encoded on pCoIV plasmids.- 8.4 Studies with Gram-positive bacteria.- 8.5 Studies on fungi.- References.- 9 Roles of aminium radical intermediates in the biotransformation of dihydropyridines, cycloalkylamines, and N,N-dimethylanilines by cytochrome P-450 enzymes.- 9.1 Introduction.- 9.2 Formation of N-O compounds.- 9.3 Ring expansion of a cyclobutylamine.- 9.4 Oxidation of dihydropyridines.- 9.5 Estimation of the oxidation potential of the active oxygenating species of P-450.- References.- 10 The role of cytochrome P-450 in the biological nuclear N-oxidation of aminoazaheterocyclic drugs and related compounds.- 10.1 Introduction.- 10.2 Observations of metabolic N-oxidation of aminoazaheterocycles.- 10.3 Enzymology of nuclear N-oxidation of aminoazaheterocycles.- 10.4 Factors involved in the N-oxidation of aminoazaheterocycles.- 10.5 Substrate-enzyme complex formation.- 10.6 Conclusions.- References.- 11 New aspects of the microsomal N-hydroxylation of benzamidines.- 11.1 Introduction.- 11.2 Aspects of metabolic investigations with amidines.- 11.3 Microsomal N-hydroxylation of N,N-unsubstituted benzamidines.- 11.4 Structure-activity relationships and mechanisms of the N-oxidative metabolism of amidines.- 11.5 Predictability of N-oxygenations by cytochrome P-450 derived from studies on amidines.- 11.6 Further transformations of benzamidoxime and benzamidine.- 11.7 Pharmacological properties of N-oxygenated metabolites.- 11.8 Genotoxic activities of benzamidoxime.- References.- 12 Studies on the N-oxidation of phentermine: evidence for an indirect pathway of N-oxidation mediated by cytochrome P-450.- 12.1 Introduction.- 12.2 Biochemical studies with microsomes.- 12.3 Biochemical studies with reconstituted systems.- 12.4 Superoxide-mediated reactions: possible mechanisms.- 12.5 Conclusions.- References.- 13 Molecular activation mechanisms involved in arylamine cytotoxicity: peroxidase products.- 13.1 Introduction.- 13.2 Enzymic mechanisms of acetaminophen bioactivation and cytotoxicity.- 13.3 Bioactivation of acetaminophen and aminophenol in hepatocytes in the presence of halides.- 13.4 Conclusions.- References.- Three Reductions and Conjugations of N-Oxygenated Compounds.- 14 Reduction and conjugation reactions of N-oxides.- 14.1 Introduction.- 14.2 Further transformations of N-oxides.- 14.3 Conclusions.- References.- 15 In vivo metabolism of N-oxides.- 15.1 Introduction.- 15.2 In vivo metabolism of tricyclic antidepressant N-oxides.- 15.3 In vivo metabolism of chlorpromazine N-oxide.- 15.4 Comparison of studies involving amitriptyline N-oxide and chlorpromazine N-oxide.- 15.5 Conclusions.- References.- 16 Purification and characterization of rat hepatic acetyltransferase.- 16.1 Introduction.- 16.2 Enzymes responsible for formation of reactive N-acetoxyarylamine metabolites.- 16.3 Conclusion.- References.- Four Bioactivation of Nitrogenous Compounds and Cell Toxicity.- 17 Metabolism and activation of nitrosamines catalysed by cytochrome P-450 isoenzymes.- 17.1 Introduction.- 17.2 Enzymology of NDMA metabolism.- 17.3 Kinetics and mechanisms of NDMA metabolism.- 17.4 The role of cytochrome P450IIE1 in the activation of NDMA.- 17.5 Regulation and functions of cytochrome P450IIE1.- 17.6 Substrate specificity and alkyl group selectivity in the metabolism of other nitrosamines.- 17.7 Metabolism of 4-(N-nitrosomethylamino)-1-(3-pyridyl)- 1-butanone (NHK).- 17.8 Organ specificity in nitrosamine metabolism and carcinogenesis.- References.- 18 Cytochrome P-450-catalysed activation of carcinogenic aromatic amines and amides.- 18.1 Introduction.- 18.2 AAF N-hydroxylation by liver microsomes.- 18.3 N-Hydroxylation of various aromatic amides.- 18.4 N-Oxidation of aromatic amines.- 18.5 Kinetic studies with microsomal preparations.- 18.6 Resolution and reconstitution of the cytochrome P-450 enzyme system.- 18.7 Conclusions.- References.- 19 Comparative biochemistry of cytochrome P-450 species responsible for the activation of mutagenic food-derived heterocyclic amines.- 19.1 Introduction.- 19.2 Activation of mutagenic food-derived heterocyclic amines by liver microsomes.- 19.3 Activation of mutagenic heterocyclic amines by human fetal liver cytochrome P-450.- 19.4 Purification and properties of P-450-D2 and P-450-D3 from liver microsomes of PCB (KC-500) treated dogs.- 19.5 Molecular cloning and expression of dog liver cytochrome P-450.- 19.6 Molecular cloning and expression of monkey liver cytochrome P-450.- 19.7 Conclusions.- References.- 20 Specificity and inducibility of cytochrome P-450 catalysing the activation of food-derived mutagenic heterocyclic amines.- 20.1 Introduction.- 20.2 The role of the P-450IA subfamily in the activation of food mutagens and other aromatic amines in various species.- 20.3 Conclusions.- References.- 21 Monoamine oxidase-mediated activation of MPTP and related compounds.- 21.1 Introduction.- 21.2 MPTP and Parkinson's disease.- 21.3 MAO B and MPTP.- 21.4 The mechanism of MPTP toxicity.- 21.5 Analogues of MPTP as substrates for MAO A and B.- 21.6 Other routes of MPTP metabolism.- 21.7 MAO B in human brain and platelets.- 21.8 Isatin, an endogenosus MAO B inhibitor.- 21.9 Effects of (-)deprenyl on longevity and Parkinson's disease.- References.- 22 Activation of aromatic amines by oxyhaemoglobin.- 22.1 Introduction.- 22.2 Formation of ferrihaemoglobin by aromatic amines.- 22.3 Fate of TMPD in the reaction with haemoglobin.- 22.4 Formation of ferrihaemoglobin by the N,N-dimethyl- and N,N,N' ,N'-tetramethyl-p-phenylenediamine radical cations.- 22.5 Influence of superoxide radicals and hydrogen peroxide on ferrihaemoglobin formation by DMPD and TMPD.- 22.6 Autoxidation of DMPD and TMPD and the influence of superoxide radicals.- 22.7 Reactions of the TMPD radical cation with GSH.- 22.8 Reactions of TMPD with red cells.- 22.9 Arylamine-induced ferrihaemoglobin formation from oxyhaemoglobin: possible reaction mechanisms.- 22.10 Reactions of arylaminyl radical cations with sulphydryl groups.- 22.11 Conclusions.- References.- 23 Relevance of primary and secondary nitroxide radicals in biological oxidations.- 23.1 Introduction.- 23.2 Primary aromatic nitroxides.- 23.3 Secondary aromatic nitroxides.- 23.4 Conclusions.- References.- 24 Molecular approaches to evaluation of the risk of aromatic amineinduced bladder cancer: smoking related carcinogen-DNA adducts in biopsied samples of human urinary bladder.- 24.1 Introduction.- 24.2 32P-postlabelling.- 24.3 Sampling of human bladder for 32P-postlabeIling analysis.- 24.4 Carcinogen-DNA adducts in human urinary bladder.- 24.5 Conclusions.- References.- 25 The role of N-oxidation by leukocytes in drug-induced agranulocytosis and other drug hypersensitivity reactions.- 25.1 Introduction.- 25.2 Metabolism of drugs by leukocytes and adverse reactions.- 25.3 Conclusions.- References.- 26 Phototoxic effects of N-oxidized drugs and related compounds.- 26.1 Introduction.- 26.2 Photobiological reactions of nitroarenes.- 26.3 Photobiological reactions of imino-N-oxides.- 26.4 Conclusions.- References.