Cytochrome P450: Role in the Metabolism and Toxicity of Drugs and Other Xenobiotics (Issues in Toxicology) - Hardcover

Hardcover

ISBN 10: 0854042741 ISBN 13: 9780854042746

Verlag: Royal Society of Chemistry, 2008

Inhaltsangabe

During half a century, cytochrome P450 in its original uniqueness as an optically "wrong" cytochrome has attracted many investigators, who have contributed to the unveiling of a bewildering multiplicity of biologically important functions of the, by now very large, superfamily of cytochrome P 450 enzymes. With its discovery in 1958 and with the advent of more refined spectroscopic methodologies, through the double wavelength spectrophotometry, the mysterious enzyme system began to reveal its secrets in a swift stream of investigative successes. As one of the most extensively studied enzyme systems worldwide the interest in cytochromes P450 very much reflects its importance in the elimination of drugs and other chemicals from the body and its role in chemical toxicity and in the aetiology of diseases such as cancer. There has been significant progress in research in this area in recent years and current books on this subject are now out of date. This much needed, new, fully up-to-date publication fills this gap and emphasises the new relevant topics that have emerged during the last decade in an easily accessible manner. The enzyme system, cytochromes P450, comprises a number of families/subfamilies, and the focus of the book is to deal with each individually, furnishing information directly relevant to scientists involved in the development of chemicals, in particular in the evaluation of their safety. The book has contributions from internationally respected scientists who are research-active in the relevant areas. The authors have made extensive use of figures and tables so that the reader can access the necessary information without always having to read the text. In addition, a very extensive, user-friendly index is a unique hallmark of the book. Part A of this monograph introduces the reader to the current knowledge of the evolutionary development of cytochrome P450 structure and function. Furthermore, it deals with the role of this enzyme in the formation of reactive intermediates. The shrewd and extensive utilisation of the molecular biology methodology very rapidly led to a vast body of enzymes calling for a classification of the plethora of different cytochromes P450 (the superfamily) into families and subfamilies. This is aptly exemplified by the ten chapters in Part B of this book, dealing with ten subfamilies and two families of cytochrome P450. Part C offers an insight into another aspect of cytochrome P450 research, namely its regulation through receptor-mediated stimuli - as opposed to enzyme induction or inhibition. The final chapter translates the current data on one of several drug metabolising systems into clinical application and highlights the role of cytochromes P450 in the treatment of neoplastic growth. The book deals extensively with each family/subfamily of the cytochromes P450 that contribute to the metabolism of xenobiotics. Essential and invaluable information is provided for the industrial research scientist working with fine chemicals, and especially those in the pharmaceutical industry, dealing with the safety evaluation of chemicals or being involved in the study of their metabolism, pharmacokinetics and toxicological properties. It should also prove of interest to Regulators concerned with the safety evaluation of chemicals, research pharmacologists and toxicologists, and postgraduate students studying drug metabolism and toxicology at an advanced level.

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Über die Autorinnen und Autoren

Costas Ioannides, BSc (University of Liverpool), PhD (University of Surrey), DSc (University of Liverpool) is currently Professor of Mechanistic Toxicology at the University of Surrey and is an established author in this area.

Costas Ioannides, BSc (University of Liverpool), PhD (University of Surrey), DSc (University of Liverpool) is currently Professor of Mechanistic Toxicology at the University of Surrey and is an established author in this area.

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One of the most extensively studied enzyme systems worldwide is the cytochromes P450, and this interest very much reflects its importance in the elimination of drugs and other chemicals from the body and its role in chemical toxicity and in the aetiology of diseases such as cancer. There has been significant progress in research in this area in recent years and current books on this subject are now out-of-date. This much needed, new, fully up-to-date publication fills this gap and emphasises the new relevant topics that have emerged during the last decade in an easily accessible manner. The enzyme system, cytochromes P450, comprises a number of families/subfamilies, and the focus of the book is to deal with each individually, furnishing information directly relevant to scientists involved in the development of chemicals, in particular in the evaluation of their safety. The book has contributions from internationally respected scientists who are research-active in the relevant areas. The authors have made extensive use of figures and tables so that the reader can access the necessary information without always having to read the text. In addition, a very extensive, user-friendly index is a unique hallmark of the book. Cytochrome P450: Role in the Metabolism and Toxicity of Drugs and other Xenobiotics deals extensively with each family/subfamily of the cytochromes P450 that contribute to the metabolism of xenobiotics. Essential and invaluable information is provided for the industrial research scientist working in the Fine Chemicals, and especially those in the Pharmaceutical industry, dealing with the safety evaluation of chemicals or being involved in the study of their metabolism, pharmacokinetics and toxicological properties. The book should also prove of interest to Regulators concerned with the safety evaluation of chemicals, research pharmacologists and toxicologists, and postgraduate students studying drug metabolism and toxicology at an advanced level.

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Cytochromes P450

Role in the Metabolism and Toxicity of Drugs and other Xenobiotics

By Costas Ioannides

The Royal Society of Chemistry

Copyright © 2008 Royal Society of Chemistry
All rights reserved.

ISBN: 978-0-85404-274-6

Contents

Part A, 
Chapter 1 Cytochrome P450 Structure and Function: An Evolutionary Perspective David F.V. Lewis and Yuko Ito, 
Chapter 2 Generation of Reactive Intermediates by Cytochromes P450 Hermann M. Bolt and Peter H. Roos, 
Part B, 
Chapter 3 The CYP1A Subfamily Bhagavatula Moorthy, 
Chapter 4 The CYP1B Subfamily Morag C.E. McFadyen and Graeme I. Murray, 
Chapter 5 The CYP2A Subfamily Hannu Raunio, Jukka Hakkola and Olavi Pelkonen, 
Chapter 6 The CYP2B Subfamily Laurent Corcos and François Berthou, 
Chapter 7 The CYP2C Subfamily Stephen S. Ferguson, Karen Black and Jonathan P. Jackson, 
Chapter 8 The CYP2D Subfamily Ulrich M. Zanger, 
Chapter 9 The CYP2E Subfamily Lowell C. Overton, Alice Hudder and Raymond F. Novak, 
Chapter 10 The CYP2F, CYP2G and CYP2J Subfamilies Qing-Yu Zhang and Xinxin Ding, 
Chapter 11 The CYP3 Family David J. Greenblatt, Ping He, Lisa L. von Moltke and Michael H. Court, 
Chapter 12 The CYP4 Family Allan E. Rettie and Edward J. Kelly, 
Part C, 
Chapter 13 Receptor-Mediated Regulation of Cytochromes P450 Kouichi Yoshinari, Eric Tien, Masahiko Negishi and Paavo Honkakoski, 
Chapter 14 Modulation of Cytochromes P450 by Phytochemicals Michael Murray, 
Chapter 15 Cytochromes P450 in Cancer Therapeutics Thomas K.H. Chang, 
Subject Index, 510, 

CHAPTER 1

Cytochrome P450 Structure and Function: An Evolutionary Perspective

DAVID F.V. LEWIS AND YUKO ITO

Table of Contents

1.1 Introduction 4
1.2 Evolutionary Aspects 7
1.3 Binding Functions of P450 11
1.4 Substrate Binding and Selectivity 15
1.5 P450 Catalysis 24
1.6 Structural Modelling of P450s 29
1.6.1 Molecular Modelling and Dynamics of P450s 30
1.6.2 Lipophilicity Relationships in P450 Substrate Binding and Selectivity 35
1.7 Conclusions 37
Abbreviations 38
Acknowledgements 39
References 39

1.1 Introduction

The cytochromes P450 constitute a superfamily of haem-thiolate enzymes which are ubiquitous in nature. Figure 1.1 shows the many fields in which P450s play important roles, thus highlighting their relevance to several branches of biological science. During the course of evolution, the P450 structure developed to bind the following entities: oxygen, carbon-based substrates, a haem group and redox partners, such as an iron-sulphur redoxin, an NADPH-dependent FAD- and FMN-containing flavoprotein reductase and cytochrome b5. In eukaryotic P450 systems, a membrane phospholipid bilayer such as that present in the smooth endoplasmic reticulum is also able to bind, as summarised in Tables 1.1 and 1.2. Mitochondrial P450s, such as CYP11 in the adrenal cortex, retain some of the prokaryotic P450 characteristics in possessing an iron-sulphur redoxin (specifically adrenodoxin) as a redox partner rather than utilising an NADPH-dependent flavoprotein reductase. This finding suggests that the mitochondria and, indeed, other cell organelles may have had bacterial origins, as has been reported previously from RNA comparisons. Over 5000 P450 sequences have been reported (Osamu Gotoh, personal communication) and it appears that these enzymes are present in all five biological kingdoms. Consequently, P450s will have undergone modifications during the course of evolution in order to adapt to the changes in environmental and cellular conditions.

P450 structures are known from X-ray crystallographic determinations and a list of these is provided in Table 1.3; surprisingly, there are relatively few differences across species ranging from bacteria to mammalia. Such differences include orientations of the B' and F helices, together with the extent of poly-peptide in the loop regions between certain helical motifs, such as those of the F-G loop and the H-I loop. Also, there is an additional N-terminal peptide of some 40 residues which serves as a membrane anchor in eukaryotic P450s, and this is absent in prokaryotic sequences. Furthermore, it is not only in the primary sequence but also in the spatial orientation of secondary structural elements with respect to the haem moiety that P450s can vary. This may explain why homology models do not always correctly reproduce the active site topographies encountered in the actual crystal structures, although a relatively high homology (ie. over 40%) should provide a fairly good match between homology models and crystal structures. Indeed, for enzymes of the CYP2C family, it is found that models of CYP2C8 and CYP2C9, based on the CYP2C5 template, do indeed match closely with the actual crystal structures, and the relationship between degree of fit and sequence homology is explored further in a following section.

The tertiary structure of P450 possesses certain well-conserved ion-pairs (such as the ExxR motif) and other features (like the polyproline motif near the N-terminus) which determine its overall folding pattern, together with various hydrogen bonded, π-π stacking and hydrophobic contacts between amino acid residues, some of which are associated with haem and substrate binding. However, certain conserved basic residues on the surface of the enzyme tend to be utilised for the binding of redox partners. These charged surface residues are largely conserved across the superfamily for redox partner binding, and this can be illustrated by the example of putidaredoxin (an iron-sulphur redoxin) binding to P450cam, and also that of adrenodoxin binding to its reductase where it is apparent that the redoxin fits closely within a depression on the reductase surface. The structure of P450 resembles a triangular prism in overall shape with the haem moiety located approximately at the centre of one triangular face. The haem group lies in a depression, which is ideally suited, in terms of shape and complementary surface residues, for the binding of redox partners such as redoxins, cytochrome b5 and reductase. However, there are certain subtle distinctions between the entire binding regions of these various redox partners and the corresponding P450 enzymes which may explain why certain redox partners tend to bind at particular surface locations on the P450 enzymes.

1.2 Evolutionary Aspects

It is generally thought that life emerged around 3.5 billion years ago, which is about a billion years after the Earth's formation (~4.55 billion years ago) although it is possible that the development of life may have occurred even earlier. P450s are ubiquitous within living systems and the enzymes have been found in all biological kingdoms, but some Archaea (early pro-karyotes) such as Escherichia coli, do not appear to contain any P450 enzymes whatsoever. However, two P450s have been isolated and crystallised from the thermophilic bacterial species Sulfolobus solfataricus and Thermus thermophilus. These organisms are apparently able to exist in the hot sulphurous conditions encountered in the thermal vents of undersea volcanic fissures, which are thought to represent the likely environment for early life formation around 3.5 billion years ago. Interestingly, the presence of iron and sulphur in such oceanic vents may have assisted in the generation of proteins requiring such elements including, for example, cytochrome P450 and its iron-sulphur ferredoxin redox partner....

Details zur Ausgabe

• Verlag: Royal Society of Chemistry
• Erscheinungsdatum: 2008
• Sprache: Englisch
• ISBN 10: 0854042741
• ISBN 13: 9780854042746
• Einband: Gebundene Ausgabe
• Anzahl der Seiten: 521
• Herausgeber: Ioannides Costas
• Kontakt zum Hersteller: Nicht verfügbar
• Verantwortliche Person: Nicht verfügbar