Cytochromes P450: Structure, Function and Mechanism (Taylor & Francis Series in Pharmaceutical Sciences)

Book Cover......Page 1
Half-Title......Page 2
Title......Page 5
Copyright......Page 6
Contents......Page 7
Acknowledgements......Page 10
Abbreviations......Page 11
Chemical Abbreviations......Page 13
Foreword......Page 15
Preface......Page 18
Captions for Colour Plates in Chapter 6......Page 19
1.1  Historical background......Page 22
1.2  Distribution......Page 24
1.3  Isolation, purification and characterization of P450s......Page 25
1.4  Spectral and related physicochemical properties......Page 28
1.4.1  Substrate-binding spectra......Page 34
1.4.2  Polarized optical spectroscopy......Page 39
1.4.3  Vibrational spectroscopy......Page 41
1.4.4.1  NMR spectroscopy......Page 47
1.4.4.2  ESR spectroscopy......Page 49
1.4.5  Mössbauer (MB) spectroscopy......Page 52
1.4.6  Extended X-ray absorption fine structure (EXAFS) spectroscopy......Page 54
1.5.1  X-ray crystallography......Page 56
1.5.2  Redox potentials and their equilibria......Page 57
1.5.3  Other physicochemical and structural studies......Page 60
2.1  Introduction......Page 72
2.2  The P450 phylogenetic tree and evolutionary aspects......Page 73
2.3  Evolutionary relationships between prokaryotic and eukaryotic P450s......Page 77
2.4  Conclusion......Page 82
2.5  P450 nomenclature......Page 83
3.2  The P450 catalytic cycle......Page 92
3.2.1  Stage 1: Substrate binding......Page 94
3.2.2  Stage 2: The first reduction......Page 96
3.2.3  Stage 3: Oxygen binding......Page 97
3.2.5  Stage 5: Product formation......Page 99
3.3  Nature of the oxygenating species......Page 100
3.4  Participation of active site amino acid residues in P450 oxygenations......Page 104
3.5  Thermodynamics of P450 substrate binding and spin-state equilibria......Page 105
3.6  The coupling of redox and spin equilibria......Page 108
3.7  Redox potential and redox interactions in the P450 system......Page 111
3.8  Interactions between redox components......Page 115
3.9  Protein-lipid interactions in the P450 system......Page 117
3.10  A proposed mechanistic scheme for the P450 catalytic cycle......Page 119
4.2  Endogenous metabolism......Page 123
4.3  Endogenous steroid hydroxylation by hepatic P450s of families CYP1, CYP2 and CYP3......Page 128
4.4  Exogenous metabolism......Page 137
4.4.1  The CYP1 family......Page 138
4.4.2  The CYP2 family......Page 150
4.4.3  The CYP2A subfamily......Page 151
4.4.4The CYP2B subfamilyEnzymes of the 2B subfamily have been extensively studied in the rat and three isoforms are known, namely, 2B1, 2B2 and 2B3 (Nelson et al., 1993). Although 2B1 and 2B2 show a 91 per cent sequence similarity, their modes of expression and regulation are different (Paine, 1991). CYP2B1 is highly inducible by phenobarbital, but is not constitutively expressed, whereas 2B2 is constitutive and only moderately induced by phenobarbital (Funae and Imaoka, 1993). The third rat form......Page 159
4.4.5 The CYP2C subfamily......Page 161
4.4.6The CYP2D subfamilyThere is considerable interest in the 2D subfamily, due to the fact that about 30 per cent (Table 4.19) of all currently-used drugs are metabolized in man by the 2D6 orthologue, which is known to exhibit genetic polymorphisms in human ethnogeographical populations (Eichelbaum and Gross, 1990). For example, poor-metabolizers of debrisoquine represent about 10 per cent of Caucasian populations. As the constitutive levels of 2D6 are low (1–2 per cent of human hepatic P450 com......Page 163
4.4.7  The CYP2E subfamily......Page 166
4.4.8  The CYP2F-CYP2K subfamilies......Page 168
4.4.9  The CYP3 family......Page 169
4.4.10  Exogenous metabolism by other CYP enzymes......Page 171
5.1  Introduction......Page 174
5.2  Induction and regulation of P450 genes......Page 178
5.3  Regulatory elements in P450 genes......Page 186
5.4  The toxic consequences of induction......Page 188
5.5  Heterologous expression systems and in vitro models......Page 192
5.6  Inhibition of cytochromes P450......Page 194
5.6.1  Competitive inhibitors......Page 195
5.6.2  Irreversible and mechanism-based inhibitors......Page 203
5.6.3  Therapeutic and agrochemical uses of P450 inhibitors......Page 206
5.6.4  Metal ions as P450 inhibitors and iron redox state preferences......Page 208
6.2  P450 modelling......Page 211
6.2.1  Physical methods......Page 212
6.2.2  P450 sequence alignment......Page 214
6.2.3  General features of P450 crystal structures and sequences......Page 228
6.2.4  Recommended procedure for homology modelling of P450s......Page 248
6.2.5  Eukaryotic P450s modelled from P450BM 3 (CYP102)......Page 250
6.2.5.1  The CYP1 family......Page 251
6.2.5.2  The CYP2 family......Page 257
6.2.5.3  The CYP3 family......Page 273
6.2.5.4  The CYP4 family......Page 274
6.2.5.5  The CYP11 family......Page 275
6.2.5.6  The CYP17 family......Page 278
6.2.5.8  The CYP101 family......Page 280
6.2.5.9  The CYP102 family......Page 281
6.3  Evaluation of P450–mediated toxicity by the COMPACT approach......Page 283
6.4  Conclusions and future prospects......Page 287
Bibliography......Page 293
References......Page 294
Index......Page 338