Main description:

The most complete and up-to-date survey of this important superfamily of enzymes, including the first ever coverage of the forms involved in steroid hormone biosynthesis. The components of the enzyme system, the reaction mechanisms involved, and the evolution and nomenclature are analyzed, as is the hepatic microsomal enzyme in a large number of species, illustrating the very wide implications for life processes.

Contents:

Section I: The Monooxygenase System.- 1 Historical Background and Description of the Cytochrome P450 Monooxygenase System.- A. Historical Introduction.- B. Cytochrome P450.- I. Multiple Forms.- II. Hemoprotein Characteristics.- III. Oxygen Activation.- IV. Uncoupling of Monooxygenations.- V. Role for Cytochrome b5.- C. Molecular Biology of Cytochrome P450.- References.- 2 NADPH-Cytochrome P450 Reductase: Function.- A. Introduction.- B. Early Characterization Studies.- I. Identification of Flavins.- II. Identification of Physiological Electron Acceptor.- III. Purification of NADPH-Cytochrome c Reductase.- C. Reduction of NADPH-Cytochrome P450 Reductase.- I. Identification of Air-Stable Semiquinone.- II. Function of Flavins in Reductase Reduction.- III. Kinetics of NADPH-Cytochrome P450 Reductase Reduction.- 1. Interflavin Electron Transfers.- 2. Mechanistic Details of Reductase Reduction.- D. Electron Transfer to Cytochrome P450 and Other Electron Carriers.- I. General Characteristics of Cytochrome P450-Dependent Reactions.- II. Electron Transfer to Cytochrome P450.- 1. Rate of Transfer from Different Reductase Reduction States.- 2. Electron Shuttling During the Monooxygenase Reaction.- III. NADPH-Cytochrome P450 Reductase Involvement in Other Reactions.- References.- 3 Protein and Gene Structure and Regulation of NADPH-Cytochrome P450 Oxidoreductase.- A. Introduction.- B. Structure of NADPH-Cytochrome P450 Oxidoreductase.- I. Membrane-Binding Domain.- II. Flavin Mononucleotide-Binding Domain.- 1. Binding of the FMN Phosphate Group.- 2. Binding of the FMN Isoalloxazine.- III. Substrate-Binding Domain.- 1. Chemical Modification, Cross-Linking, and Site-Directed Mutagenesis.- 2. Chemical Modification and Site-Directed Mutagenesis of Cytochrome P450.- IV. Flavin Adenine Dinucleotide-Binding Domain.- V. NADPH-Binding Domain.- 1. Dinucleotide-Binding Site.- 2. Role of Cysteine in NADPH Binding.- 3. Binding of 2?-Phosphate of NADPH.- VI. Interactions Between Domains.- C. Structure of the NADPH-Cytochrome P450 Oxidoreductase Gene.- D. Regulation of NADPH-Cytochrome P450 Oxidoreductase Gene Expression.- I. Induction.- II. Developmental Regulation.- References.- 4 Localization of Cytochrome P450 in Membranes: Mitochondria.- A. Cytochrome P450 in Mitochondria.- B. Topology of Cytochrome P450 Molecules in the Mitochondrial Inner Membrane.- C. Biosynthesis of Mitochondrial Cytochrome P450s as Precursor Forms.- D. Import of Cytochrome P450 Precursors into Mitochondria and Their Processing to Mature Membrane-Bound Forms.- References.- 5 Localization of Cytochrome P450 in Membranes: Reconstituted Systems.- A. Introduction.- B. Soluble Reconstituted Systems.- I. Formation of the Catalytically Active Cytochrome P450: Reductase Complex.- 1. Binary Complex Formation.- 2. Dissociation of the Preformed Cytochrome P450: Reductase Complex.- 3. Association of the Cytochrome P450: Reductase Complex.- 4. Reconstitution of Maximum Cytochrome P450 Supported Activity Without Lipid.- II. Effects on the Reconstituted Soluble Cytochrome P450: Reductase System.- 1. Detergent-Mediated Effects.- 2. Organic Solvent-Mediated Effects.- 3. Effects of Cytochrome b5.- 4. Self-Association of Monomers.- 5. Electrostatic Interactions Between Cytochrome P450 and Reductase.- C. Vesicular Reconstituted Systems.- D. Conclusions.- References.- Section II: The Monooxygenase Reactions.- 6 Metabolic Reactions: Types of Reactions of Cytochrome P450 Enzymes.- A. Introduction.- B. General Features of Cytochrome P450 Catalysis.- C. Specific Oxidative Reactions.- I. Carbon Hydroxylation.- II. Heteroatom Oxygenation.- III. Heteroatom Release.- IV. Rearrangements Related to Heteroatom Oxidations.- V. Oxidations of Ti-Systems.- VI. Reactions Involving Hypervalent Oxygen Substrates.- D. Reductive Reactions.- E. Conclusions.- References.- 7 Metabolic Reactions: Mechanisms of Substrate Oxygenation.- A. Introduction.- B. Substrate Interaction with Cytochrome P450.- I. Relationship Between Spectral Changes and Spin State.- II. Substrate-Induced Spin State Equilibrium Shift.- III. Substrate-Induced Redox Potential Shift.- C. Reduction Control by the Spin/Redox Couple Ill.- D. Ternary Cytochrome P450-Dioxygen-Substrate Complex.- E. Cleavage of the Dioxygen Bond.- F. Regulation of Substrate Turnover.- References.- 8 Liver Cytochrome P450 Metabolism of Endogenous Steroid Hormones, Bile Acids, and Fatty Acids.- A. Introduction.- B. Hydroxylation of Neutral Steroids (Steroid Hormones) by Liver Cytochromes P450.- I. Substrate Specificity.- II. Developmental and Hormonal Regulation.- III. Significance of Steroid Hydroxylations.- C. Hydroxylations of Bile Acids.- I. Bile Acid Biosynthesis: Physiological Implications of Bile Acid Hydrophobicity.- II. Bile Acid Hydroxylase Cytochromes P450.- D. Hydroxylations of Fatty Acids.- E. Oxidation of Ethanol and Other Low Molecular Weight Compounds.- F. Cytochrome P450 Mediated Endogenous Metabolism in Other Systems.- G. Conclusion.- References.- 9 Metabolic Reactions: Role of Cytochrome P450 in the Formation of Reactive Oxygen Species.- A. Definition of Reactive Oxygen.- B. Reactive Oxygen Generation During Drug Metabolism.- C. Formation of Drug Radicals During Metabolism by Cytochrome P450.- D. Lipid Peroxidation Catalyzed by Cytochrome P450.- E. Conclusions.- References.- 10 Cytochrome P450 Structure and Function.- A. Introduction.- B. Analysis of the Tertiary Structure of Cytochrome P450cam.- C. Approaches to Computation of Three-Dimensional Models of Cytochromes P450.- I. General Approach.- II. Examples of Three-Dimensional Protein Models.- III. Three-Dimensional Models of Cytochromes P450.- IV. Limitations.- D. Problems Addressable with Three-Dimensional Models of Cytochromes P450.- References.- 11 Structure of Cytochrome P450: Heme-Binding Site and Heme Reactivity.- A. Introduction.- B. Cytochrome P450cam (CYP101).- C. Sequence Alignments.- D. Mutagenesis Studies.- E. Topological Analysis by Covalent Heme Modification.- I. Terminal Olefins and Acetylenes.- II. Phenylhydrazine and Phenyldiazene.- III. 4-Alkyl-1,4-dihydropyridines.- F. Topological Information from Substrate Specificity.- I. Cytochrome P4501A1 (CYP1A1).- II. Cytochrome P4502D6 (CYP2D6).- G. Conclusions.- References.- 12 Cytochrome P450: Probes of Active Site Residues.- A. Introduction.- B. Substrate-Binding Site Probes.- I. Substrate-Binding Site-Directed Probes.- 1. Affinity and Photoaffinity Probes.- 2. Suicide Substrates.- II. Amino Acid Residue Modifications.- III. Substrate Regio- and Stereoselectivity.- IV. Comparisons of Cytochrome P450 Primary Structures.- C. Conclusion.- References.- 13 Structural Models for Substrates and Inhibitors of Cytochrome P450 Enzymes.- A. Introduction.- B. Three-Dimensional Structure of the Active Site as a Basis for Substrate and Inhibitor Design.- I. X-Ray Structure of Cytochrome P450cam.- II. "Homology Building"Section I: The Monooxygenase System.- 1 Historical Background and Description of the Cytochrome P450 Monooxygenase System.- A. Historical Introduction.- B. Cytochrome P450.- I. Multiple Forms.- II. Hemoprotein Characteristics.- III. Oxygen Activation.- IV. Uncoupling of Monooxygenations.- V. Role for Cytochrome b5.- C. Molecular Biology of Cytochrome P450.- References.- 2 NADPH-Cytochrome P450 Reductase: Function.- A. Introduction.- B. Early Characterization Studies.- I. Identification of Flavins.- II. Identification of Physiological Electron Acceptor.- III. Purification of NADPH-Cytochrome c Reductase.- C. Reduction of NADPH-Cytochrome P450 Reductase.- I. Identification of Air-Stable Semiquinone.- II. Function of Flavins in Reductase Reduction.- III. Kinetics of NADPH-Cytochrome P450 Reductase Reduction.- 1. Interflavin Electron Transfers.- 2. Mechanistic Details of Reductase Reduction.- D. Electron Transfer to Cytochrome P450 and Other Electron Carriers.- I. General Characteristics of Cytochrome P450-Dependent Reactions.- II. Electron Transfer to Cytochrome P450.- 1. Rate of Transfer from Different Reductase Reduction States.- 2. Electron Shuttling During the Monooxygenase Reaction.- III. NADPH-Cytochrome P450 Reductase Involvement in Other Reactions.- References.- 3 Protein and Gene Structure and Regulation of NADPH-Cytochrome P450 Oxidoreductase.- A. Introduction.- B. Structure of NADPH-Cytochrome P450 Oxidoreductase.- I. Membrane-Binding Domain.- II. Flavin Mononucleotide-Binding Domain.- 1. Binding of the FMN Phosphate Group.- 2. Binding of the FMN Isoalloxazine.- III. Substrate-Binding Domain.- 1. Chemical Modification, Cross-Linking, and Site-Directed Mutagenesis.- 2. Chemical Modification and Site-Directed Mutagenesis of Cytochrome P450.- IV. Flavin Adenine Dinucleotide-Binding Domain.- V. NADPH-Binding Domain.- 1. Dinucleotide-Binding Site.- 2. Role of Cysteine in NADPH Binding.- 3. Binding of 2?-Phosphate of NADPH.- VI. Interactions Between Domains.- C. Structure of the NADPH-Cytochrome P450 Oxidoreductase Gene.- D. Regulation of NADPH-Cytochrome P450 Oxidoreductase Gene Expression.- I. Induction.- II. Developmental Regulation.- References.- 4 Localization of Cytochrome P450 in Membranes: Mitochondria.- A. Cytochrome P450 in Mitochondria.- B. Topology of Cytochrome P450 Molecules in the Mitochondrial Inner Membrane.- C. Biosynthesis of Mitochondrial Cytochrome P450s as Precursor Forms.- D. Import of Cytochrome P450 Precursors into Mitochondria and Their Processing to Mature Membrane-Bound Forms.- References.- 5 Localization of Cytochrome P450 in Membranes: Reconstituted Systems.- A. Introduction.- B. Soluble Reconstituted Systems.- I. Formation of the Catalytically Active Cytochrome P450: Reductase Complex.- 1. Binary Complex Formation.- 2. Dissociation of the Preformed Cytochrome P450: Reductase Complex.- 3. Association of the Cytochrome P450: Reductase Complex.- 4. Reconstitution of Maximum Cytochrome P450 Supported Activity Without Lipid.- II. Effects on the Reconstituted Soluble Cytochrome P450: Reductase System.- 1. Detergent-Mediated Effects.- 2. Organic Solvent-Mediated Effects.- 3. Effects of Cytochrome b5.- 4. Self-Association of Monomers.- 5. Electrostatic Interactions Between Cytochrome P450 and Reductase.- C. Vesicular Reconstituted Systems.- D. Conclusions.- References.- Section II: The Monooxygenase Reactions.- 6 Metabolic Reactions: Types of Reactions of Cytochrome P450 Enzymes.- A. Introduction.- B. General Features of Cytochrome P450 Catalysis.- C. Specific Oxidative Reactions.- I. Carbon Hydroxylation.- II. Heteroatom Oxygenation.- III. Heteroatom Release.- IV. Rearrangements Related to Heteroatom Oxidations.- V. Oxidations of Ti-Systems.- VI. Reactions Involving Hypervalent Oxygen Substrates.- D. Reductive Reactions.- E. Conclusions.- References.- 7 Metabolic Reactions: Mechanisms of Substrate Oxygenation.- A. Introduction.- B. Substrate Interaction with Cytochrome P450.- I. Relationship Between Spectral Changes and Spin State.- II. Substrate-Induced Spin State Equilibrium Shift.- III. Substrate-Induced Redox Potential Shift.- C. Reduction Control by the Spin/Redox Couple Ill.- D. Ternary Cytochrome P450-Dioxygen-Substrate Complex.- E. Cleavage of the Dioxygen Bond.- F. Regulation of Substrate Turnover.- References.- 8 Liver Cytochrome P450 Metabolism of Endogenous Steroid Hormones, Bile Acids, and Fatty Acids.- A. Introduction.- B. Hydroxylation of Neutral Steroids (Steroid Hormones) by Liver Cytochromes P450.- I. Substrate Specificity.- II. Developmental and Hormonal Regulation.- III. Significance of Steroid Hydroxylations.- C. Hydroxylations of Bile Acids.- I. Bile Acid Biosynthesis: Physiological Implications of Bile Acid Hydrophobicity.- II. Bile Acid Hydroxylase Cytochromes P450.- D. Hydroxylations of Fatty Acids.- E. Oxidation of Ethanol and Other Low Molecular Weight Compounds.- F. Cytochrome P450 Mediated Endogenous Metabolism in Other Systems.- G. Conclusion.- References.- 9 Metabolic Reactions: Role of Cytochrome P450 in the Formation of Reactive Oxygen Species.- A. Definition of Reactive Oxygen.- B. Reactive Oxygen Generation During Drug Metabolism.- C. Formation of Drug Radicals During Metabolism by Cytochrome P450.- D. Lipid Peroxidation Catalyzed by Cytochrome P450.- E. Conclusions.- References.- 10 Cytochrome P450 Structure and Function.- A. Introduction.- B. Analysis of the Tertiary Structure of Cytochrome P450cam.- C. Approaches to Computation of Three-Dimensional Models of Cytochromes P450.- I. General Approach.- II. Examples of Three-Dimensional Protein Models.- III. Three-Dimensional Models of Cytochromes P450.- IV. Limitations.- D. Problems Addressable with Three-Dimensional Models of Cytochromes P450.- References.- 11 Structure of Cytochrome P450: Heme-Binding Site and Heme Reactivity.- A. Introduction.- B. Cytochrome P450cam (CYP101).- C. Sequence Alignments.- D. Mutagenesis Studies.- E. Topological Analysis by Covalent Heme Modification.- I. Terminal Olefins and Acetylenes.- II. Phenylhydrazine and Phenyldiazene.- III. 4-Alkyl-1,4-dihydropyridines.- F. Topological Information from Substrate Specificity.- I. Cytochrome P4501A1 (CYP1A1).- II. Cytochrome P4502D6 (CYP2D6).- G. Conclusions.- References.- 12 Cytochrome P450: Probes of Active Site Residues.- A. Introduction.- B. Substrate-Binding Site Probes.- I. Substrate-Binding Site-Directed Probes.- 1. Affinity and Photoaffinity Probes.- 2. Suicide Substrates.- II. Amino Acid Residue Modifications.- III. Substrate Regio- and Stereoselectivity.- IV. Comparisons of Cytochrome P450 Primary Structures.- C. Conclusion.- References.- 13 Structural Models for Substrates and Inhibitors of Cytochrome P450 Enzymes.- A. Introduction.- B. Three-Dimensional Structure of the Active Site as a Basis for Substrate and Inhibitor Design.- I. X-Ray Structure of Cytochrome P450cam.- II. "Homology Building"Section I: The Monooxygenase System.- 1 Historical Background and Description of the Cytochrome P450 Monooxygenase System.- A. Historical Introduction.- B. Cytochrome P450.- I. Multiple Forms.- II. Hemoprotein Characteristics.- III. Oxygen Activation.- IV. Uncoupling of Monooxygenations.- V. Role for Cytochrome b5.- C. Molecular Biology of Cytochrome P450.- References.- 2 NADPH-Cytochrome P450 Reductase: Function.- A. Introduction.- B. Early Characterization Studies.- I. Identification of Flavins.- II. Identification of Physiological Electron Acceptor.- III. Purification of NADPH-Cytochrome c Reductase.- C. Reduction of NADPH-Cytochrome P450 Reductase.- I. Identification of Air-Stable Semiquinone.- II. Function of Flavins in Reductase Reduction.- III. Kinetics of NADPH-Cytochrome P450 Reductase Reduction.- 1. Interflavin Electron Transfers.- 2. Mechanistic Details of Reductase Reduction.- D. Electron Transfer to Cytochrome P450 and Other Electron Carriers.- I. General Characteristics of Cytochrome P450-Dependent Reactions.- II. Electron Transfer to Cytochrome P450.- 1. Rate of Transfer from Different Reductase Reduction States.- 2. Electron Shuttling During the Monooxygenase Reaction.- III. NADPH-Cytochrome P450 Reductase Involvement in Other Reactions.- References.- 3 Protein and Gene Structure and Regulation of NADPH-Cytochrome P450 Oxidoreductase.- A. Introduction.- B. Structure of NADPH-Cytochrome P450 Oxidoreductase.- I. Membrane-Binding Domain.- II. Flavin Mononucleotide-Binding Domain.- 1. Binding of the FMN Phosphate Group.- 2. Binding of the FMN Isoalloxazine.- III. Substrate-Binding Domain.- 1. Chemical Modification, Cross-Linking, and Site-Directed Mutagenesis.- 2. Chemical Modification and Site-Directed Mutagenesis of Cytochrome P450.- IV. Flavin Adenine Dinucleotide-Binding Domain.- V. NADPH-Binding Domain.- 1. Dinucleotide-Binding Site.- 2. Role of Cysteine in NADPH Binding.- 3. Binding of 2?-Phosphate of NADPH.- VI. Interactions Between Domains.- C. Structure of the NADPH-Cytochrome P450 Oxidoreductase Gene.- D. Regulation of NADPH-Cytochrome P450 Oxidoreductase Gene Expression.- I. Induction.- II. Developmental Regulation.- References.- 4 Localization of Cytochrome P450 in Membranes: Mitochondria.- A. Cytochrome P450 in Mitochondria.- B. Topology of Cytochrome P450 Molecules in the Mitochondrial Inner Membrane.- C. Biosynthesis of Mitochondrial Cytochrome P450s as Precursor Forms.- D. Import of Cytochrome P450 Precursors into Mitochondria and Their Processing to Mature Membrane-Bound Forms.- References.- 5 Localization of Cytochrome P450 in Membranes: Reconstituted Systems.- A. Introduction.- B. Soluble Reconstituted Systems.- I. Formation of the Catalytically Active Cytochrome P450: Reductase Complex.- 1. Binary Complex Formation.- 2. Dissociation of the Preformed Cytochrome P450: Reductase Complex.- 3. Association of the Cytochrome P450: Reductase Complex.- 4. Reconstitution of Maximum Cytochrome P450 Supported Activity Without Lipid.- II. Effects on the Reconstituted Soluble Cytochrome P450: Reductase System.- 1. Detergent-Mediated Effects.- 2. Organic Solvent-Mediated Effects.- 3. Effects of Cytochrome b5.- 4. Self-Association of Monomers.- 5. Electrostatic Interactions Between Cytochrome P450 and Reductase.- C. Vesicular Reconstituted Systems.- D. Conclusions.- References.- Section II: The Monooxygenase Reactions.- 6 Metabolic Reactions: Types of Reactions of Cytochrome P450 Enzymes.- A. Introduction.- B. General Features of Cytochrome P450 Catalysis.- C. Specific Oxidative Reactions.- I. Carbon Hydroxylation.- II. Heteroatom Oxygenation.- III. Heteroatom Release.- IV. Rearrangements Related to Heteroatom Oxidations.- V. Oxidations of Ti-Systems.- VI. Reactions Involving Hypervalent Oxygen Substrates.- D. Reductive Reactions.- E. Conclusions.- References.- 7 Metabolic Reactions: Mechanisms of Substrate Oxygenation.- A. Introduction.- B. Substrate Interaction with Cytochrome P450.- I. Relationship Between Spectral Changes and Spin State.- II. Substrate-Induced Spin State Equilibrium Shift.- III. Substrate-Induced Redox Potential Shift.- C. Reduction Control by the Spin/Redox Couple Ill.- D. Ternary Cytochrome P450-Dioxygen-Substrate Complex.- E. Cleavage of the Dioxygen Bond.- F. Regulation of Substrate Turnover.- References.- 8 Liver Cytochrome P450 Metabolism of Endogenous Steroid Hormones, Bile Acids, and Fatty Acids.- A. Introduction.- B. Hydroxylation of Neutral Steroids (Steroid Hormones) by Liver Cytochromes P450.- I. Substrate Specificity.- II. Developmental and Hormonal Regulation.- III. Significance of Steroid Hydroxylations.- C. Hydroxylations of Bile Acids.- I. Bile Acid Biosynthesis: Physiological Implications of Bile Acid Hydrophobicity.- II. Bile Acid Hydroxylase Cytochromes P450.- D. Hydroxylations of Fatty Acids.- E. Oxidation of Ethanol and Other Low Molecular Weight Compounds.- F. Cytochrome P450 Mediated Endogenous Metabolism in Other Systems.- G. Conclusion.- References.- 9 Metabolic Reactions: Role of Cytochrome P450 in the Formation of Reactive Oxygen Species.- A. Definition of Reactive Oxygen.- B. Reactive Oxygen Generation During Drug Metabolism.- C. Formation of Drug Radicals During Metabolism by Cytochrome P450.- D. Lipid Peroxidation Catalyzed by Cytochrome P450.- E. Conclusions.- References.- 10 Cytochrome P450 Structure and Function.- A. Introduction.- B. Analysis of the Tertiary Structure of Cytochrome P450cam.- C. Approaches to Computation of Three-Dimensional Models of Cytochromes P450.- I. General Approach.- II. Examples of Three-Dimensional Protein Models.- III. Three-Dimensional Models of Cytochromes P450.- IV. Limitations.- D. Problems Addressable with Three-Dimensional Models of Cytochromes P450.- References.- 11 Structure of Cytochrome P450: Heme-Binding Site and Heme Reactivity.- A. Introduction.- B. Cytochrome P450cam (CYP101).- C. Sequence Alignments.- D. Mutagenesis Studies.- E. Topological Analysis by Covalent Heme Modification.- I. Terminal Olefins and Acetylenes.- II. Phenylhydrazine and Phenyldiazene.- III. 4-Alkyl-1,4-dihydropyridines.- F. Topological Information from Substrate Specificity.- I. Cytochrome P4501A1 (CYP1A1).- II. Cytochrome P4502D6 (CYP2D6).- G. Conclusions.- References.- 12 Cytochrome P450: Probes of Active Site Residues.- A. Introduction.- B. Substrate-Binding Site Probes.- I. Substrate-Binding Site-Directed Probes.- 1. Affinity and Photoaffinity Probes.- 2. Suicide Substrates.- II. Amino Acid Residue Modifications.- III. Substrate Regio- and Stereoselectivity.- IV. Comparisons of Cytochrome P450 Primary Structures.- C. Conclusion.- References.- 13 Structural Models for Substrates and Inhibitors of Cytochrome P450 Enzymes.- A. Introduction.- B. Three-Dimensional Structure of the Active Site as a Basis for Substrate and Inhibitor Design.- I. X-Ray Structure of Cytochrome P450cam.- II. "Homology Building" of the Active Site of Mammalian Enzymes.- C. Approaches to Design Substrate and Inhibitor Models.- I. Empirical Models.- II. Computer-Aided Molecular Design of Pharmacophor Models.- 1. Quantitative Structure Activity Relationship (QSAR) Analysis.- 2. Molecular Modeling.- 3. Molecular Modeling of Substrates and Inhibitors of Cytochrome P450 2D6.- D. Conclusions.- References.- Section III: Forms of Microsomal P.- 14 Cytochrome P450 Evolution and Nomenclature.- A. Evolution of Cytochromes P450.- B. Cytochrome P450 Nomenclature.- I. Definitions of Families and Subfamilies.- II. Orthologous Genes.- III. Allelic Variants.- IV. The Cytochrome P450 Superfamily.- References.- 15 Cytochrome P450 in Rodents.- A. Introduction.- B. Rat Cytochrome P450 Forms.- I. Forms Isolated.- 1. CYP1A1, 1A2.- 2. CYP2A1, 2A2.- 3. CYP2B1, 2B2.- 4. CYP2C6, 2C7, 2C11, 2C12, 2C13.- 5. CYP2D1, 2D2.- 6. CYP2E1.- 7. CYP3A1, 3A2.- 8. CYP4A1, 4A2, 4A3.- 9. Other Forms of Cytochrome P450.- II. Catalytic Properties of Rat Cytochrome P450.- III. Changes in Rat Hepatic Cytochrome P450 by Treatment with Chemicals and Under Different Pathophysiological Conditions.- C. Rabbit and Mouse Cytochromes P450.- References.- 16 Cytochrome P450 in Humans.- A. Introduction.- B. CYP1A Subfamily.- I. CYP1A1.- II. CYP1A2.- C. CYP2A Subfamily.- D. CYP2B Subfamily.- E. CYP2C Subfamily.- F. CYP2D Subfamily.- G. CYP2E Subfamily.- H. CYP2F Subfamily.- I. CYP3A Subfamily.- References.- 17 Avian Cytochrome P450.- A. Introduction.- B. Phenobarbital-Inducible Cytochrome P450 in Avians.- I. Historical Perspective.- II. Hepatic Mixed Function Oxidase Activities Induced by Phenobarbital Treatment in Avians.- 1. Enzyme Activities.- 2. Embryonic Response.- III. Identification of Phenobarbital-Inducible Forms of Cytochrome P450.- 1. Cytochrome P450 2H1 and 2H2.- 2. Other Phenobarbital-Induced Forms of Cytochrome P450.- IV. Mechanism of Induction of Cytochrome P450 2H1/2.- 1. Properties of Inducers.- 2. Expression of Cytochrome P450 2H1/2 Protein and mRNAs.- 3. Role of Heme in Expression of Cytochrome P450 2H1/2.- 4. Effect of Protein Synthesis Inhibitors on Expression of Cytochrome P450 2H1/2.- 5. Mechanism of Coordinate Induction of Cytochrome P450 and ALAS.- C. Planar Poly cyclic Aromatic Hydrocarbon-Inducible Cytochrome P450 in Avians.- I. Historical Perspective.- II. Hepatic Mixed Function Oxidase Activities Induced by Planar Polycyclic Aromatic Hydrocarbons in Avians.- 1. Enzyme Activities.- III. Identification of Planar Polycyclic Aromatic-Inducible Forms of Avian Cytochrome P450.- IV. Mechanism of Induction of Cytochrome P4501A.- D. Acetone-and Alcohol-Inducible Cytochrome P450 in Avians.- I. Hepatic Mixed Function Oxidase Activities Induced by Acetone or Ethanol in Avians.- II. Identification of Acetone-Inducible Forms of Cytochrome P450.- E. Additional Avian Forms of Cytochrome P450.- I. Dexamethasone-Inducible Cytochrome P450.- II. Vitamin D Hydroxylase.- III. Steroid Metabolism.- F. Conclusions.- References.- 18 Cytochrome P450 Forms in Fish.- A. Introduction.- B. Microsomal Cytochrome P450 in Fish.- C. Cytochrome P450 Forms in Liver.- D. Cytochrome P450 Form Relationships.- I. Gene Family 1.- 1. Subfamily 1A.- 2. Multiple 1A Genes?.- 3. Cytochrome P450 1A Regulation.- II. Gene Family 2.- 1. Subfamily 2B.- 2. Subfamily 2E.- III. Gene Family 3.- E. Extrahepatic Cytochrome P450.- I. Cytochrome P450 1A (Distribution).- II. Cytochrome P450LM2/KM2.- F. Conclusion.- References.- 19 Cytochrome P450 in Plants.- A. Introduction.- B. Components and Distribution.- C. Forms of Cytochrome P450.- I. Physiological Substrates.- 1. Phenylpropanoids.- 2. Terpenes.- 3. Fatty Acids.- 4. Cyanogenic Glucosides.- II. Metabolism of Xenobiotics.- D. Conclusion.- References.- 20 Cytochrome P450 in Insects.- A. Introduction.- B. Structures of Insect Cytochrome P450.- I. CYP6A1.- II. CYP6A2.- III. CYP6B1.- IV. CYP4C1.- V. CYP4D1.- VI. NADPH Cytochrome P450 Reductase.- C. Functions of Insect Cytochrome P450.- I. Metabolism of Foreign Compounds.- II. Ecdysteroid Metabolism.- 1. Ecdysone 20-Monooxygenase.- 2. Biosynthesis of Ecdysone Precursors.- III. Juvenile Hormone Biosynthesis.- IV. Pheromone Biosynthesis.- V. Fatty Acid Metabolism.- D. Cytochrome P450 in Drosophila melanogaster.- E. Insect Systems for the Expression of Cytochrome P450 Genes.- I. Baculovirus.- II. P-Element Transformation of Drosophila.- References.- 21 Cytochrome P450 in Unicellular Organisms.- A. Introduction.- B. Cytochromes P450 from Bacteria.- I. Camphor-Hydroxylating Cytochrome P450 from Pseudomonas putida.- II. Cytochrome P450 Linalool 8-Methyl Hydroxylase from Pseudomonas putida (icognita).- III. Cytochrome P450 Fatty Hydroxylase from Bacillus megaterium.- IV. Cytochromes P450 from Actinomycetes.- 1. Herbicide-Inducible Cytochromes P450 from Streptomyces grisoleus.- 2. Soybean Flour-Induced Cytrochrome P450 from Streptomyces griseus.- 3. Cytochrome P450 6-Deoxyerythronolide B Hydroxylase from Saccharopolyspora erythracea.- 4. Compactin-Inducible Cytochrome P450 Hydroxylase from Streptomyces carbophilus.- 5. Veratrole-Inducible Cytochrome P450 from Streptomyces setonii.- C. Cytochromes P450 from Eukaryotic Microorganisms.- I. Cytochromes P450 from Yeasts.- 1. Cytochrome P450 14?-Lanosterol Demethylase.- 2. Alkane-Inducible Cytochrome P450 Monooxygenases.- 3. Cytochrome P450 Involved in Spore Wall Maturation.- II. Cytochromes P450 from Fungi.- 1. Cytochrome P450 Benzoate-p-hydroxylase from Aspergillus niger.- 2. Cytochrome P450 Pisatin Demethylase from Nectria haematococca.- 3. Cytochrome P450 Monooxygenases from Fusarium oxysporium.- 4. 11?-Progesterone Hydroxylase from Rhizopium nigricans.- 5. Cycloheximide-Inducible Cytochrome P450 from Neurospora crassa.- 6. Cytochrome P450 Monooxygenases from Cunninghamella Species.- D. Conclusions.- References.- 22 Extrahepatic Microsomal Forms: Olfactory Cytochrome P450.- A. Introduction.- B. Olfactory Cytochrome P450 of Rabbits.- I. NMa and NMb.- II. Other Forms.- C. Olfactory Cytochrome P450 in Other Species.- I. Cytochrome P450olf1 and Cytochrome P450olf2.- II. Other Forms.- D. Future Prospects.- References.- 23 Extrahepatic Microsomal Forms: Gastrointestinal Cytochromes P450, Assessment and Evaluation.- A. Introduction.- B. Human Colon Drug Metabolism.- I. Microsomal Activities.- II. Cytochrome P450.- C. Human Colon Tumor Cell Drug Metabolism.- I. Microsomal Activities.- II. Intact Cell Assays.- III. Cytochromes P450.- D. Discussion.- References.- 24 Extrahepatic Microsomal Forms: Lung Microsomal Cytochrome P450 Isozymes.- A. Introduction.- B. Lung Microsomal Cytochrome P450 Dependent Monooxygenases.- I. Species Differences in Lung Cytochrome P450 Dependent Monooxygenase Activities.- C. Lung Microsomal Cytochrome P450 Isozymes.- I. Rabbit Lung Microsomal Cytochromes P450.- 1. Properties and Regulation of Rabbit Lung Cytochrome P4502B4 (P450LgM2).- 2. Comparison of Properties of Sheep and Rabbit Lung Cytochrome P450LgM2.- 3. Properties and Regulation of Rabbit Lung Cytochrome P4504B1 (P450LgM5).- 4. Properties and Regulation of Rabbit Lung Cytochrome P450LgM6 (P4501A1).- 5. Properties and Regulation of Rabbit Lung Cytochromes P450PGw, P450P-2 (P4504A4).- 6. Substrate Specificities of Rabbit Lung Cytochrome P450 Isozymes.- II. Rat Lung Microsomal Cytochrome P450 Isozymes.- 1. Regulation and Characteristics of Rat Lung Cytochrome P4502B1.- 2. Regulation and Characteristics of Rat Lung Cytochromes P4501A1 and P4501A2.- 3. Regulation and Characteristics of Rat Lung Cytochrome P4502A3.- 4. Regulation and Characteristics of Rat Lung Cytochrome P4504B1.- References.- 25 Extrahepatic Microsomal Forms: Brain Cytochrome P450.- A. Introduction.- B. Quantitation and Identification of Specific Forms of Brain Cytochrome P450.- 1. Hepatic Microsomal Forms of Cytochrome P450.- 2. Aromatase.- 3. Estrogen 2-Hydroxylase.- 4. 5?-Androstane-3ss, 17ss#8221; of the Active Site of Mammalian Enzymes.- C. Approaches to Design Substrate and Inhibitor Models.- I. Empirical Models.- II. Computer-Aided Molecular Design of Pharmacophor Models.- 1. Quantitative Structure Activity Relationship (QSAR) Analysis.- 2. Molecular Modeling.- 3. Molecular Modeling of Substrates and Inhibitors of Cytochrome P450 2D6.- D. Conclusions.- References.- Section III: Forms of Microsomal P.- 14 Cytochrome P450 Evolution and Nomenclature.- A. Evolution of Cytochromes P450.- B. Cytochrome P450 Nomenclature.- I. Definitions of Families and Subfamilies.- II. Orthologous Genes.- III. Allelic Variants.- IV. The Cytochrome P450 Superfamily.- References.- 15 Cytochrome P450 in Rodents.- A. Introduction.- B. Rat Cytochrome P450 Forms.- I. Forms Isolated.- 1. CYP1A1, 1A2.- 2. CYP2A1, 2A2.- 3. CYP2B1, 2B2.- 4. CYP2C6, 2C7, 2C11, 2C12, 2C13.- 5. CYP2D1, 2D2.- 6. CYP2E1.- 7. CYP3A1, 3A2.- 8. CYP4A1, 4A2, 4A3.- 9. Other Forms of Cytochrome P450.- II. Catalytic Properties of Rat Cytochrome P450.- III. Changes in Rat Hepatic Cytochrome P450 by Treatment with Chemicals and Under Different Pathophysiological Conditions.- C. Rabbit and Mouse Cytochromes P450.- References.- 16 Cytochrome P450 in Humans.- A. Introduction.- B. CYP1A Subfamily.- I. CYP1A1.- II. CYP1A2.- C. CYP2A Subfamily.- D. CYP2B Subfamily.- E. CYP2C Subfamily.- F. CYP2D Subfamily.- G. CYP2E Subfamily.- H. CYP2F Subfamily.- I. CYP3A Subfamily.- References.- 17 Avian Cytochrome P450.- A. Introduction.- B. Phenobarbital-Inducible Cytochrome P450 in Avians.- I. Historical Perspective.- II. Hepatic Mixed Function Oxidase Activities Induced by Phenobarbital Treatment in Avians.- 1. Enzyme Activities.- 2. Embryonic Response.- III. Identification of Phenobarbital-Inducible Forms of Cytochrome P450.- 1. Cytochrome P450 2H1 and 2H2.- 2. Other Phenobarbital-Induced Forms of Cytochrome P450.- IV. Mechanism of Induction of Cytochrome P450 2H1/2.- 1. Properties of Inducers.- 2. Expression of Cytochrome P450 2H1/2 Protein and mRNAs.- 3. Role of Heme in Expression of Cytochrome P450 2H1/2.- 4. Effect of Protein Synthesis Inhibitors on Expression of Cytochrome P450 2H1/2.- 5. Mechanism of Coordinate Induction of Cytochrome P450 and ALAS.- C. Planar Poly cyclic Aromatic Hydrocarbon-Inducible Cytochrome P450 in Avians.- I. Historical Perspective.- II. Hepatic Mixed Function Oxidase Activities Induced by Planar Polycyclic Aromatic Hydrocarbons in Avians.- 1. Enzyme Activities.- III. Identification of Planar Polycyclic Aromatic-Inducible Forms of Avian Cytochrome P450.- IV. Mechanism of Induction of Cytochrome P4501A.- D. Acetone-and Alcohol-Inducible Cytochrome P450 in Avians.- I. Hepatic Mixed Function Oxidase Activities Induced by Acetone or Ethanol in Avians.- II. Identification of Acetone-Inducible Forms of Cytochrome P450.- E. Additional Avian Forms of Cytochrome P450.- I. Dexamethasone-Inducible Cytochrome P450.- II. Vitamin D Hydroxylase.- III. Steroid Metabolism.- F. Conclusions.- References.- 18 Cytochrome P450 Forms in Fish.- A. Introduction.- B. Microsomal Cytochrome P450 in Fish.- C. Cytochrome P450 Forms in Liver.- D. Cytochrome P450 Form Relationships.- I. Gene Family 1.- 1. Subfamily 1A.- 2. Multiple 1A Genes?.- 3. Cytochrome P450 1A Regulation.- II. Gene Family 2.- 1. Subfamily 2B.- 2. Subfamily 2E.- III. Gene Family 3.- E. Extrahepatic Cytochrome P450.- I. Cytochrome P450 1A (Distribution).- II. Cytochrome P450LM2/KM2.- F. Conclusion.- References.- 19 Cytochrome P450 in Plants.- A. Introduction.- B. Components and Distribution.- C. Forms of Cytochrome P450.- I. Physiological Substrates.- 1. Phenylpropanoids.- 2. Terpenes.- 3. Fatty Acids.- 4. Cyanogenic Glucosides.- II. Metabolism of Xenobiotics.- D. Conclusion.- References.- 20 Cytochrome P450 in Insects.- A. Introduction.- B. Structures of Insect Cytochrome P450.- I. CYP6A1.- II. CYP6A2.- III. CYP6B1.- IV. CYP4C1.- V. CYP4D1.- VI. NADPH Cytochrome P450 Reductase.- C. Functions of Insect Cytochrome P450.- I. Metabolism of Foreign Compounds.- II. Ecdysteroid Metabolism.- 1. Ecdysone 20-Monooxygenase.- 2. Biosynthesis of Ecdysone Precursors.- III. Juvenile Hormone Biosynthesis.- IV. Pheromone Biosynthesis.- V. Fatty Acid Metabolism.- D. Cytochrome P450 in Drosophila melanogaster.- E. Insect Systems for the Expression of Cytochrome P450 Genes.- I. Baculovirus.- II. P-Element Transformation of Drosophila.- References.- 21 Cytochrome P450 in Unicellular Organisms.- A. Introduction.- B. Cytochromes P450 from Bacteria.- I. Camphor-Hydroxylating Cytochrome P450 from Pseudomonas putida.- II. Cytochrome P450 Linalool 8-Methyl Hydroxylase from Pseudomonas putida (icognita).- III. Cytochrome P450 Fatty Hydroxylase from Bacillus megaterium.- IV. Cytochromes P450 from Actinomycetes.- 1. Herbicide-Inducible Cytochromes P450 from Streptomyces grisoleus.- 2. Soybean Flour-Induced Cytrochrome P450 from Streptomyces griseus.- 3. Cytochrome P450 6-Deoxyerythronolide B Hydroxylase from Saccharopolyspora erythracea.- 4. Compactin-Inducible Cytochrome P450 Hydroxylase from Streptomyces carbophilus.- 5. Veratrole-Inducible Cytochrome P450 from Streptomyces setonii.- C. Cytochromes P450 from Eukaryotic Microorganisms.- I. Cytochromes P450 from Yeasts.- 1. Cytochrome P450 14?-Lanosterol Demethylase.- 2. Alkane-Inducible Cytochrome P450 Monooxygenases.- 3. Cytochrome P450 Involved in Spore Wall Maturation.- II. Cytochromes P450 from Fungi.- 1. Cytochrome P450 Benzoate-p-hydroxylase from Aspergillus niger.- 2. Cytochrome P450 Pisatin Demethylase from Nectria haematococca.- 3. Cytochrome P450 Monooxygenases from Fusarium oxysporium.- 4. 11?-Progesterone Hydroxylase from Rhizopium nigricans.- 5. Cycloheximide-Inducible Cytochrome P450 from Neurospora crassa.- 6. Cytochrome P450 Monooxygenases from Cunninghamella Species.- D. Conclusions.- References.- 22 Extrahepatic Microsomal Forms: Olfactory Cytochrome P450.- A. Introduction.- B. Olfactory Cytochrome P450 of Rabbits.- I. NMa and NMb.- II. Other Forms.- C. Olfactory Cytochrome P450 in Other Species.- I. Cytochrome P450olf1 and Cytochrome P450olf2.- II. Other Forms.- D. Future Prospects.- References.- 23 Extrahepatic Microsomal Forms: Gastrointestinal Cytochromes P450, Assessment and Evaluation.- A. Introduction.- B. Human Colon Drug Metabolism.- I. Microsomal Activities.- II. Cytochrome P450.- C. Human Colon Tumor Cell Drug Metabolism.- I. Microsomal Activities.- II. Intact Cell Assays.- III. Cytochromes P450.- D. Discussion.- References.- 24 Extrahepatic Microsomal Forms: Lung Microsomal Cytochrome P450 Isozymes.- A. Introduction.- B. Lung Microsomal Cytochrome P450 Dependent Monooxygenases.- I. Species Differences in Lung Cytochrome P450 Dependent Monooxygenase Activities.- C. Lung Microsomal Cytochrome P450 Isozymes.- I. Rabbit Lung Microsomal Cytochromes P450.- 1. Properties and Regulation of Rabbit Lung Cytochrome P4502B4 (P450LgM2).- 2. Comparison of Properties of Sheep and Rabbit Lung Cytochrome P450LgM2.- 3. Properties and Regulation of Rabbit Lung Cytochrome P4504B1 (P450LgM5).- 4. Properties and Regulation of Rabbit Lung Cytochrome P450LgM6 (P4501A1).- 5. Properties and Regulation of Rabbit Lung Cytochromes P450PGw, P450P-2 (P4504A4).- 6. Substrate Specificities of Rabbit Lung Cytochrome P450 Isozymes.- II. Rat Lung Microsomal Cytochrome P450 Isozymes.- 1. Regulation and Characteristics of Rat Lung Cytochrome P4502B1.- 2. Regulation and Characteristics of Rat Lung Cytochromes P4501A1 and P4501A2.- 3. Regulation and Characteristics of Rat Lung Cytochrome P4502A3.- 4. Regulation and Characteristics of Rat Lung Cytochrome P4504B1.- References.- 25 Extrahepatic Microsomal Forms: Brain Cytochrome P450.- A. Introduction.- B. Quantitation and Identification of Specific Forms of Brain Cytochrome P450.- 1. Hepatic Microsomal Forms of Cytochrome P450.- 2. Aromatase.- 3. Estrogen 2-Hydroxylase.- 4. 5?-Androstane-3ss, 17ssSection I: The Monooxygenase System.- 1 Historical Background and Description of the Cytochrome P450 Monooxygenase System.- A. Historical Introduction.- B. Cytochrome P450.- I. Multiple Forms.- II. Hemoprotein Characteristics.- III. Oxygen Activation.- IV. Uncoupling of Monooxygenations.- V. Role for Cytochrome b5.- C. Molecular Biology of Cytochrome P450.- References.- 2 NADPH-Cytochrome P450 Reductase: Function.- A. Introduction.- B. Early Characterization Studies.- I. Identification of Flavins.- II. Identification of Physiological Electron Acceptor.- III. Purification of NADPH-Cytochrome c Reductase.- C. Reduction of NADPH-Cytochrome P450 Reductase.- I. Identification of Air-Stable Semiquinone.- II. Function of Flavins in Reductase Reduction.- III. Kinetics of NADPH-Cytochrome P450 Reductase Reduction.- 1. Interflavin Electron Transfers.- 2. Mechanistic Details of Reductase Reduction.- D. Electron Transfer to Cytochrome P450 and Other Electron Carriers.- I. General Characteristics of Cytochrome P450-Dependent Reactions.- II. Electron Transfer to Cytochrome P450.- 1. Rate of Transfer from Different Reductase Reduction States.- 2. Electron Shuttling During the Monooxygenase Reaction.- III. NADPH-Cytochrome P450 Reductase Involvement in Other Reactions.- References.- 3 Protein and Gene Structure and Regulation of NADPH-Cytochrome P450 Oxidoreductase.- A. Introduction.- B. Structure of NADPH-Cytochrome P450 Oxidoreductase.- I. Membrane-Binding Domain.- II. Flavin Mononucleotide-Binding Domain.- 1. Binding of the FMN Phosphate Group.- 2. Binding of the FMN Isoalloxazine.- III. Substrate-Binding Domain.- 1. Chemical Modification, Cross-Linking, and Site-Directed Mutagenesis.- 2. Chemical Modification and Site-Directed Mutagenesis of Cytochrome P450.- IV. Flavin Adenine Dinucleotide-Binding Domain.- V. NADPH-Binding Domain.- 1. Dinucleotide-Binding Site.- 2. Role of Cysteine in NADPH Binding.- 3. Binding of 2?-Phosphate of NADPH.- VI. Interactions Between Domains.- C. Structure of the NADPH-Cytochrome P450 Oxidoreductase Gene.- D. Regulation of NADPH-Cytochrome P450 Oxidoreductase Gene Expression.- I. Induction.- II. Developmental Regulation.- References.- 4 Localization of Cytochrome P450 in Membranes: Mitochondria.- A. Cytochrome P450 in Mitochondria.- B. Topology of Cytochrome P450 Molecules in the Mitochondrial Inner Membrane.- C. Biosynthesis of Mitochondrial Cytochrome P450s as Precursor Forms.- D. Import of Cytochrome P450 Precursors into Mitochondria and Their Processing to Mature Membrane-Bound Forms.- References.- 5 Localization of Cytochrome P450 in Membranes: Reconstituted Systems.- A. Introduction.- B. Soluble Reconstituted Systems.- I. Formation of the Catalytically Active Cytochrome P450: Reductase Complex.- 1. Binary Complex Formation.- 2. Dissociation of the Preformed Cytochrome P450: Reductase Complex.- 3. Association of the Cytochrome P450: Reductase Complex.- 4. Reconstitution of Maximum Cytochrome P450 Supported Activity Without Lipid.- II. Effects on the Reconstituted Soluble Cytochrome P450: Reductase System.- 1. Detergent-Mediated Effects.- 2. Organic Solvent-Mediated Effects.- 3. Effects of Cytochrome b5.- 4. Self-Association of Monomers.- 5. Electrostatic Interactions Between Cytochrome P450 and Reductase.- C. Vesicular Reconstituted Systems.- D. Conclusions.- References.- Section II: The Monooxygenase Reactions.- 6 Metabolic Reactions: Types of Reactions of Cytochrome P450 Enzymes.- A. Introduction.- B. General Features of Cytochrome P450 Catalysis.- C. Specific Oxidative Reactions.- I. Carbon Hydroxylation.- II. Heteroatom Oxygenation.- III. Heteroatom Release.- IV. Rearrangements Related to Heteroatom Oxidations.- V. Oxidations of Ti-Systems.- VI. Reactions Involving Hypervalent Oxygen Substrates.- D. Reductive Reactions.- E. Conclusions.- References.- 7 Metabolic Reactions: Mechanisms of Substrate Oxygenation.- A. Introduction.- B. Substrate Interaction with Cytochrome P450.- I. Relationship Between Spectral Changes and Spin State.- II. Substrate-Induced Spin State Equilibrium Shift.- III. Substrate-Induced Redox Potential Shift.- C. Reduction Control by the Spin/Redox Couple Ill.- D. Ternary Cytochrome P450-Dioxygen-Substrate Complex.- E. Cleavage of the Dioxygen Bond.- F. Regulation of Substrate Turnover.- References.- 8 Liver Cytochrome P450 Metabolism of Endogenous Steroid Hormones, Bile Acids, and Fatty Acids.- A. Introduction.- B. Hydroxylation of Neutral Steroids (Steroid Hormones) by Liver Cytochromes P450.- I. Substrate Specificity.- II. Developmental and Hormonal Regulation.- III. Significance of Steroid Hydroxylations.- C. Hydroxylations of Bile Acids.- I. Bile Acid Biosynthesis: Physiological Implications of Bile Acid Hydrophobicity.- II. Bile Acid Hydroxylase Cytochromes P450.- D. Hydroxylations of Fatty Acids.- E. Oxidation of Ethanol and Other Low Molecular Weight Compounds.- F. Cytochrome P450 Mediated Endogenous Metabolism in Other Systems.- G. Conclusion.- References.- 9 Metabolic Reactions: Role of Cytochrome P450 in the Formation of Reactive Oxygen Species.- A. Definition of Reactive Oxygen.- B. Reactive Oxygen Generation During Drug Metabolism.- C. Formation of Drug Radicals During Metabolism by Cytochrome P450.- D. Lipid Peroxidation Catalyzed by Cytochrome P450.- E. Conclusions.- References.- 10 Cytochrome P450 Structure and Function.- A. Introduction.- B. Analysis of the Tertiary Structure of Cytochrome P450cam.- C. Approaches to Computation of Three-Dimensional Models of Cytochromes P450.- I. General Approach.- II. Examples of Three-Dimensional Protein Models.- III. Three-Dimensional Models of Cytochromes P450.- IV. Limitations.- D. Problems Addressable with Three-Dimensional Models of Cytochromes P450.- References.- 11 Structure of Cytochrome P450: Heme-Binding Site and Heme Reactivity.- A. Introduction.- B. Cytochrome P450cam (CYP101).- C. Sequence Alignments.- D. Mutagenesis Studies.- E. Topological Analysis by Covalent Heme Modification.- I. Terminal Olefins and Acetylenes.- II. Phenylhydrazine and Phenyldiazene.- III. 4-Alkyl-1,4-dihydropyridines.- F. Topological Information from Substrate Specificity.- I. Cytochrome P4501A1 (CYP1A1).- II. Cytochrome P4502D6 (CYP2D6).- G. Conclusions.- References.- 12 Cytochrome P450: Probes of Active Site Residues.- A. Introduction.- B. Substrate-Binding Site Probes.- I. Substrate-Binding Site-Directed Probes.- 1. Affinity and Photoaffinity Probes.- 2. Suicide Substrates.- II. Amino Acid Residue Modifications.- III. Substrate Regio- and Stereoselectivity.- IV. Comparisons of Cytochrome P450 Primary Structures.- C. Conclusion.- References.- 13 Structural Models for Substrates and Inhibitors of Cytochrome P450 Enzymes.- A. Introduction.- B. Three-Dimensional Structure of the Active Site as a Basis for Substrate and Inhibitor Design.- I. X-Ray Structure of Cytochrome P450cam.- II. "Homology Building" of the Active Site of Mammalian Enzymes.- C. Approaches to Design Substrate and Inhibitor Models.- I. Empirical Models.- II. Computer-Aided Molecular Design of Pharmacophor Models.- 1. Quantitative Structure Activity Relationship (QSAR) Analysis.- 2. Molecular Modeling.- 3. Molecular Modeling of Substrates and Inhibitors of Cytochrome P450 2D6.- D. Conclusions.- References.- Section III: Forms of Microsomal P.- 14 Cytochrome P450 Evolution and Nomenclature.- A. Evolution of Cytochromes P450.- B. Cytochrome P450 Nomenclature.- I. Definitions of Families and Subfamilies.- II. Orthologous Genes.- III. Allelic Variants.- IV. The Cytochrome P450 Superfamily.- References.- 15 Cytochrome P450 in Rodents.- A. Introduction.- B. Rat Cytochrome P450 Forms.- I. Forms Isolated.- 1. CYP1A1, 1A2.- 2. CYP2A1, 2A2.- 3. CYP2B1, 2B2.- 4. CYP2C6, 2C7, 2C11, 2C12, 2C13.- 5. CYP2D1, 2D2.- 6. CYP2E1.- 7. CYP3A1, 3A2.- 8. CYP4A1, 4A2, 4A3.- 9. Other Forms of Cytochrome P450.- II. Catalytic Properties of Rat Cytochrome P450.- III. Changes in Rat Hepatic Cytochrome P450 by Treatment with Chemicals and Under Different Pathophysiological Conditions.- C. Rabbit and Mouse Cytochromes P450.- References.- 16 Cytochrome P450 in Humans.- A. Introduction.- B. CYP1A Subfamily.- I. CYP1A1.- II. CYP1A2.- C. CYP2A Subfamily.- D. CYP2B Subfamily.- E. CYP2C Subfamily.- F. CYP2D Subfamily.- G. CYP2E Subfamily.- H. CYP2F Subfamily.- I. CYP3A Subfamily.- References.- 17 Avian Cytochrome P450.- A. Introduction.- B. Phenobarbital-Inducible Cytochrome P450 in Avians.- I. Historical Perspective.- II. Hepatic Mixed Function Oxidase Activities Induced by Phenobarbital Treatment in Avians.- 1. Enzyme Activities.- 2. Embryonic Response.- III. Identification of Phenobarbital-Inducible Forms of Cytochrome P450.- 1. Cytochrome P450 2H1 and 2H2.- 2. Other Phenobarbital-Induced Forms of Cytochrome P450.- IV. Mechanism of Induction of Cytochrome P450 2H1/2.- 1. Properties of Inducers.- 2. Expression of Cytochrome P450 2H1/2 Protein and mRNAs.- 3. Role of Heme in Expression of Cytochrome P450 2H1/2.- 4. Effect of Protein Synthesis Inhibitors on Expression of Cytochrome P450 2H1/2.- 5. Mechanism of Coordinate Induction of Cytochrome P450 and ALAS.- C. Planar Poly cyclic Aromatic Hydrocarbon-Inducible Cytochrome P450 in Avians.- I. Historical Perspective.- II. Hepatic Mixed Function Oxidase Activities Induced by Planar Polycyclic Aromatic Hydrocarbons in Avians.- 1. Enzyme Activities.- III. Identification of Planar Polycyclic Aromatic-Inducible Forms of Avian Cytochrome P450.- IV. Mechanism of Induction of Cytochrome P4501A.- D. Acetone-and Alcohol-Inducible Cytochrome P450 in Avians.- I. Hepatic Mixed Function Oxidase Activities Induced by Acetone or Ethanol in Avians.- II. Identification of Acetone-Inducible Forms of Cytochrome P450.- E. Additional Avian Forms of Cytochrome P450.- I. Dexamethasone-Inducible Cytochrome P450.- II. Vitamin D Hydroxylase.- III. Steroid Metabolism.- F. Conclusions.- References.- 18 Cytochrome P450 Forms in Fish.- A. Introduction.- B. Microsomal Cytochrome P450 in Fish.- C. Cytochrome P450 Forms in Liver.- D. Cytochrome P450 Form Relationships.- I. Gene Family 1.- 1. Subfamily 1A.- 2. Multiple 1A Genes?.- 3. Cytochrome P450 1A Regulation.- II. Gene Family 2.- 1. Subfamily 2B.- 2. Subfamily 2E.- III. Gene Family 3.- E. Extrahepatic Cytochrome P450.- I. Cytochrome P450 1A (Distribution).- II. Cytochrome P450LM2/KM2.- F. Conclusion.- References.- 19 Cytochrome P450 in Plants.- A. Introduction.- B. Components and Distribution.- C. Forms of Cytochrome P450.- I. Physiological Substrates.- 1. Phenylpropanoids.- 2. Terpenes.- 3. Fatty Acids.- 4. Cyanogenic Glucosides.- II. Metabolism of Xenobiotics.- D. Conclusion.- References.- 20 Cytochrome P450 in Insects.- A. Introduction.- B. Structures of Insect Cytochrome P450.- I. CYP6A1.- II. CYP6A2.- III. CYP6B1.- IV. CYP4C1.- V. CYP4D1.- VI. NADPH Cytochrome P450 Reductase.- C. Functions of Insect Cytochrome P450.- I. Metabolism of Foreign Compounds.- II. Ecdysteroid Metabolism.- 1. Ecdysone 20-Monooxygenase.- 2. Biosynthesis of Ecdysone Precursors.- III. Juvenile Hormone Biosynthesis.- IV. Pheromone Biosynthesis.- V. Fatty Acid Metabolism.- D. Cytochrome P450 in Drosophila melanogaster.- E. Insect Systems for the Expression of Cytochrome P450 Genes.- I. Baculovirus.- II. P-Element Transformation of Drosophila.- References.- 21 Cytochrome P450 in Unicellular Organisms.- A. Introduction.- B. Cytochromes P450 from Bacteria.- I. Camphor-Hydroxylating Cytochrome P450 from Pseudomonas putida.- II. Cytochrome P450 Linalool 8-Methyl Hydroxylase from Pseudomonas putida (icognita).- III. Cytochrome P450 Fatty Hydroxylase from Bacillus megaterium.- IV. Cytochromes P450 from Actinomycetes.- 1. Herbicide-Inducible Cytochromes P450 from Streptomyces grisoleus.- 2. Soybean Flour-Induced Cytrochrome P450 from Streptomyces griseus.- 3. Cytochrome P450 6-Deoxyerythronolide B Hydroxylase from Saccharopolyspora erythracea.- 4. Compactin-Inducible Cytochrome P450 Hydroxylase from Streptomyces carbophilus.- 5. Veratrole-Inducible Cytochrome P450 from Streptomyces setonii.- C. Cytochromes P450 from Eukaryotic Microorganisms.- I. Cytochromes P450 from Yeasts.- 1. Cytochrome P450 14?-Lanosterol Demethylase.- 2. Alkane-Inducible Cytochrome P450 Monooxygenases.- 3. Cytochrome P450 Involved in Spore Wall Maturation.- II. Cytochromes P450 from Fungi.- 1. Cytochrome P450 Benzoate-p-hydroxylase from Aspergillus niger.- 2. Cytochrome P450 Pisatin Demethylase from Nectria haematococca.- 3. Cytochrome P450 Monooxygenases from Fusarium oxysporium.- 4. 11?-Progesterone Hydroxylase from Rhizopium nigricans.- 5. Cycloheximide-Inducible Cytochrome P450 from Neurospora crassa.- 6. Cytochrome P450 Monooxygenases from Cunninghamella Species.- D. Conclusions.- References.- 22 Extrahepatic Microsomal Forms: Olfactory Cytochrome P450.- A. Introduction.- B. Olfactory Cytochrome P450 of Rabbits.- I. NMa and NMb.- II. Other Forms.- C. Olfactory Cytochrome P450 in Other Species.- I. Cytochrome P450olf1 and Cytochrome P450olf2.- II. Other Forms.- D. Future Prospects.- References.- 23 Extrahepatic Microsomal Forms: Gastrointestinal Cytochromes P450, Assessment and Evaluation.- A. Introduction.- B. Human Colon Drug Metabolism.- I. Microsomal Activities.- II. Cytochrome P450.- C. Human Colon Tumor Cell Drug Metabolism.- I. Microsomal Activities.- II. Intact Cell Assays.- III. Cytochromes P450.- D. Discussion.- References.- 24 Extrahepatic Microsomal Forms: Lung Microsomal Cytochrome P450 Isozymes.- A. Introduction.- B. Lung Microsomal Cytochrome P450 Dependent Monooxygenases.- I. Species Differences in Lung Cytochrome P450 Dependent Monooxygenase Activities.- C. Lung Microsomal Cytochrome P450 Isozymes.- I. Rabbit Lung Microsomal Cytochromes P450.- 1. Properties and Regulation of Rabbit Lung Cytochrome P4502B4 (P450LgM2).- 2. Comparison of Properties of Sheep and Rabbit Lung Cytochrome P450LgM2.- 3. Properties and Regulation of Rabbit Lung Cytochrome P4504B1 (P450LgM5).- 4. Properties and Regulation of Rabbit Lung Cytochrome P450LgM6 (P4501A1).- 5. Properties and Regulation of Rabbit Lung Cytochromes P450PGw, P450P-2 (P4504A4).- 6. Substrate Specificities of Rabbit Lung Cytochrome P450 Isozymes.- II. Rat Lung Microsomal Cytochrome P450 Isozymes.- 1. Regulation and Characteristics of Rat Lung Cytochrome P4502B1.- 2. Regulation and Characteristics of Rat Lung Cytochromes P4501A1 and P4501A2.- 3. Regulation and Characteristics of Rat Lung Cytochrome P4502A3.- 4. Regulation and Characteristics of Rat Lung Cytochrome P4504B1.- References.- 25 Extrahepatic Microsomal Forms: Brain Cytochrome P450.- A. Introduction.- B. Quantitation and Identification of Specific Forms of Brain Cytochrome P450.- 1. Hepatic Microsomal Forms of Cytochrome P450.- 2. Aromatase.- 3. Estrogen 2-Hydroxylase.- 4. 5?-Androstane-3ss, 17ss-Diol Hydroxylase.- C. Induction of Brain Cytochrome P450.- 1. Xenobiotic Induction.- 2. Hormonal Induction.- D. Mitochondrial Cytochromes P450.- E. Novel Physiological Functions.- F. Potential Toxicological Consequences.- G. Conclusions.- References.- 26 Cytochrome P450 in Primary and Permanent Liver Cell Cultures.- A. Introduction.- B. Primary Hepatocyte Cultures.- I. Decrease of Cytochrome P450 in Primary Hepatocyte Cultures.- II. Measures for Maintaining Cytochrome P450.- 1. Composition of Culture Media.- 2. Cocultures and Extracellular Matrix.- III. Induction in Primary Hepatocyte Cultures.- C. Permanent Cultures of Hepatic Cells.- I. H4IIEC3 Rat Hepatoma Cells.- II. HepG2 Human Hepatoma Cells.- III. Prospects for Developing Metabolically Competent Cell Lines.- References.- 27 Cytochromes P450 in Genetically Engineered Cell Cultures: The Gene Technological Approach.- A. The Gene Technological Approach to Cytochrome P450.- B. Genetically Engineered Cell Culture Systems.- I. Escherichia coli.- II. Yeast.- III. Mammalian Cells.- C. Advantages and Limitations.- References.- Section IV: Modulation of Cytochrome P450 Levels.- 28 Genetics: Animal and Human Cytochrome P450 Polymorphisms.- A. Introduction.- B. Polymorphisms in Cytochrome P450 Genes.- C. Debrisoquine Polymorphism.- I. Phenotypic Studies.- II. Biochemical and Molecular Biological Studies.- III. Molecular Basis of the Poor Metaboliser Phenotype in Humans.- IV. Molecular Basis of the Debrisoquine Metabolism Deficiency in the DA Rat.- V. Interethnic Variation in Debrisoquine Metabolism.- VI. Consequences of the Poor Metaboliser Phenotype.- D. Mephenytoin Polymorphism.- I. Phenotypic Studies.- II. Biochemical and Molecular Biological Studies.- E. Other Polymorphisms in Human Cytochrome P450 Genes.- F. Conclusion.- References.- 29 Hormonal Regulation of Cytochrome P450 in Rat Liver.- A. Introduction.- B. Gonadal Hormones.- C. Growth Hormone.- D. Insulin.- E. Thyroid Hormone.- F. Species Differences and Organ-Specific Regulation.- References.- 30 Age- and Gender-Related Expression of Rat Liver Cytochrome P450.- A. Introduction and Background.- B. Hormonal Regulation of Constitutive Cytochromes P450.- C. Cytochrome P450a and RLM2 (CYP2A Subfamily).- D. Cytochromes P450b, P450c, P450d and P450e (CYP1A and CYP2B Subfamilies).- E. Cytochromes P450f, P450g, P450h, P450i and P450k (CYP2C Subfamily).- I. Cytochrome P450f (CYP2C7).- II. Cytochrome P450g (CYP2C13).- III. Cytochrome P450h (CYP2C11).- IV. Cytochrome P450i (CYP2C12).- V. Cytochrome P450k (CYP2C6).- F. Cytochrome P450j (CYP2E Subfamily).- G. Cytochromes P450p and P4501 (CYP3A Subfamily).- H. Additional Sex-Specific Cytochromes P450.- References.- 31 Changes in Cytochrome P450 in Senescence.- A. Introduction.- B. Cytochrome P450 Content.- I. Hepatic.- II. Extrahepatic.- C. Specific Cytochrome P450 Isozymes.- I. Structural Studies.- II. Enzymatic Studies.- 1. Hepatic.- 2. Extrahepatic.- III. Molecular Studies.- D. Induction.- E. Conclusions.- References.- 32 Regulation of Cytochrome P450 Expression.- A. Introduction.- B. Cytochrome P450 1 Family.- I. cis-Acting Regulatory Elements.- II. trans-Acting Regulatory Factors.- C. Cytochrome P450 2B Family.- D. Cytochrome P450 4A Family.- E. Conclusions.- References.- 33 Induction of Cytochromes P450 1 and P450 2 by Xenobiotics.- A. Introduction.- B. Historical Perspectives.- C. Induction of CYP1A1.- I. Need for New Protein Synthesis.- II. 2,3,7,8-Tetrachlorodibenzo-p-dioxin, Polycyclic Hydrocarbons and Cytochrome P450.- 1. TCDD Receptor or Ah Receptor.- 2. Polycyclic Hydrocarbon-Binding Protein or 4S Protein.- D. CYP1A1 and CYP1A2 Genes.- I. Induction of the Cytochrome P450 1 Subfamily by Polycyclic Hydrocarbons and Dioxins.- II. Regulation of the CYP1A1 Gene.- 1. Regulation by Polycyclic Hydrocarbons.- III. Further Notes on the Regulation of CYP1A2.- E. Cytochrome P450 2 Family.- I. CYP2B1 and CYP2B2.- 1. Cytochrome P450 2B Genes and Transcription.- 2. Phenobarbital Induction of Cytochrome P450 in Bacillus megaterium.- 3. Mechanism of Action of Phenobarbital as an Inducer of CYP2B.- F. CYP2E1.- I. Regulation of CYP2E1.- G. Conclusion.- References.- Section V: Chemical Modification, Protein-Protein and Protein-Lipid Interaction.- 34 Protein-Protein Interactions.- A. Introduction.- B. Microsomal Cytochrome P450 Monooxygenases.- I. Cytochrome b5 Interactions.- II. NADPH-Cytochrome P450 Reductase Interactions.- III. Cytochrome P450 Interactions.- C. Effects of Ionic Strength.- D. Role of the Hydrophobic Membrane-Binding Domain.- E. Mitochondrial P450 Monooxygenases.- I. Adrenodoxin-Adrenodoxin Reductase Interactions.- II. Adrenodoxin-CYP11A1 Interactions.- F. Conclusions.- References.- 35 Chemical Probes of Cytochrome P450 Structure.- A. Introduction.- B. Identification and Localization of Functionally Important Regions of Cytochrome P450.- I. Regions and Residues Forming the Substrate-Binding Site of Cytochrome P450.- 1. Modification of Cysteine Residues.- 2. Modification of Histidine Residues.- 3. Modification of Amino Groups.- 4. Modification of Tyrosine Residues.- II. Residues Involved in Cytochrome P450/Electron Donor Interactions.- 1. Microsomal Cytochrome P450 Systems.- 2. Mitochondrial Cytochrome P450 Systems.- 3. Bacterial Cytochrome P450 Systems.- C. Characterization of Structurally Important Regions of Cytochrome P450.- I. Accessibilities of Residues and Regions.- II. Location of Selected Amino Acids Residues with Respect to Heme.- III. Location of Selected Residues with Respect to the Microsomal Membrane.- D. Concluding Remarks.- References.- 36 Posttranslational Modification of Cytochrome P450.- A. Introduction.- B. Phosphorylation of Cholesterol 7?-Hydroxylase (CYP7).- C. Phosphorylation of Phenobarbital-Inducible (CYP2B4) and Other Forms of Microsomal Cytochrome P450 with Broad Substrate Specificity.- I. Phosphorylation of Cytochrome P450.- II. Possible Role of Phosphorylation.- D. Phosphorylation of Mitochondrial Forms of Cytochrome P450.- E. Processing of Newly Synthesized Cytochrome P450 upon Incorporation into Membranes.- F. Conclusions.- References.- 37 Lipid-Protein Interactions.- A. Introduction.- B. Liver Microsomal Systems.- I. Structural Aspects.- II. Dynamic Aspects.- III. Functional Aspects.- IV. Protein-Lipid Interactions.- V. Physiological Implications.- C. Adrenal Mitochondrial Systems.- I. Structural Aspects.- II. Functional Aspects.- References.- Section VI: Biosynthetic Forms of Cytochrome P.- 38 Cholesterol 7?-Hydroxylase and 12?-Hydroxylase.- A. Introduction.- B. Cholesterol 7?-Hydroxylase (CYP7).- I. Physiological Significance.- II. Purification and Properties.- III. Cloning of cDNA and Gene Structure.- IV. Regulation.- C. 12?-Hydroxylase.- I. Physiological Significance.- II. Assay Method.- III. Purification and Properties.- IV. Regulation.- D. Concluding Remarks.- References.- 39 Tissue-Specific Regulation of Aromatase Cytochrome P450 (CYP19) Expression.- A. Introduction.- B. Comparison of the cDNA Insert Encoding Human Aromatase Cytochrome P450 with That of Other Species.- C. Characterization of the Aromatase Cytochrome P450 Gene.- D. Regulation of Aromatase Gene Expression in Human Ovary.- E. Regulation of Aromatase Expression in Human Adipose.- F. Tissue-Specific Regulation of Human P450arom Expression Is Achieved Using Alternative Promoters.- References.- 40 Lanosterol 14a-Demethylase (Cytochrome P45014DM).- A. Introduction.- B. Molecular Properties.- C. Catalytic Features.- D. Structure of Substrate Necessary for Interaction with Cytochrome P45014DM.- E. Substrate Specificities of Sterol Demethylase Cytochromes P450 of Different Organisms.- F. Summary and Outlook.- References.- 41 Steroid 11ss-Hydroxylase Isozymes (CYP11B1 and CYP11B2).- A. Zonal Distribution of 11ss-Hydroxylase Activity.- B. Biochemistry.- C. Genetics.- D. Genetic Disorders of 11ss-Hydroxylase Isozymes.- I. Steroid 11ss#223;-Diol Hydroxylase.- C. Induction of Brain Cytochrome P450.- 1. Xenobiotic Induction.- 2. Hormonal Induction.- D. Mitochondrial Cytochromes P450.- E. Novel Physiological Functions.- F. Potential Toxicological Consequences.- G. Conclusions.- References.- 26 Cytochrome P450 in Primary and Permanent Liver Cell Cultures.- A. Introduction.- B. Primary Hepatocyte Cultures.- I. Decrease of Cytochrome P450 in Primary Hepatocyte Cultures.- II. Measures for Maintaining Cytochrome P450.- 1. Composition of Culture Media.- 2. Cocultures and Extracellular Matrix.- III. Induction in Primary Hepatocyte Cultures.- C. Permanent Cultures of Hepatic Cells.- I. H4IIEC3 Rat Hepatoma Cells.- II. HepG2 Human Hepatoma Cells.- III. Prospects for Developing Metabolically Competent Cell Lines.- References.- 27 Cytochromes P450 in Genetically Engineered Cell Cultures: The Gene Technological Approach.- A. The Gene Technological Approach to Cytochrome P450.- B. Genetically Engineered Cell Culture Systems.- I. Escherichia coli.- II. Yeast.- III. Mammalian Cells.- C. Advantages and Limitations.- References.- Section IV: Modulation of Cytochrome P450 Levels.- 28 Genetics: Animal and Human Cytochrome P450 Polymorphisms.- A. Introduction.- B. Polymorphisms in Cytochrome P450 Genes.- C. Debrisoquine Polymorphism.- I. Phenotypic Studies.- II. Biochemical and Molecular Biological Studies.- III. Molecular Basis of the Poor Metaboliser Phenotype in Humans.- IV. Molecular Basis of the Debrisoquine Metabolism Deficiency in the DA Rat.- V. Interethnic Variation in Debrisoquine Metabolism.- VI. Consequences of the Poor Metaboliser Phenotype.- D. Mephenytoin Polymorphism.- I. Phenotypic Studies.- II. Biochemical and Molecular Biological Studies.- E. Other Polymorphisms in Human Cytochrome P450 Genes.- F. Conclusion.- References.- 29 Hormonal Regulation of Cytochrome P450 in Rat Liver.- A. Introduction.- B. Gonadal Hormones.- C. Growth Hormone.- D. Insulin.- E. Thyroid Hormone.- F. Species Differences and Organ-Specific Regulation.- References.- 30 Age- and Gender-Related Expression of Rat Liver Cytochrome P450.- A. Introduction and Background.- B. Hormonal Regulation of Constitutive Cytochromes P450.- C. Cytochrome P450a and RLM2 (CYP2A Subfamily).- D. Cytochromes P450b, P450c, P450d and P450e (CYP1A and CYP2B Subfamilies).- E. Cytochromes P450f, P450g, P450h, P450i and P450k (CYP2C Subfamily).- I. Cytochrome P450f (CYP2C7).- II. Cytochrome P450g (CYP2C13).- III. Cytochrome P450h (CYP2C11).- IV. Cytochrome P450i (CYP2C12).- V. Cytochrome P450k (CYP2C6).- F. Cytochrome P450j (CYP2E Subfamily).- G. Cytochromes P450p and P4501 (CYP3A Subfamily).- H. Additional Sex-Specific Cytochromes P450.- References.- 31 Changes in Cytochrome P450 in Senescence.- A. Introduction.- B. Cytochrome P450 Content.- I. Hepatic.- II. Extrahepatic.- C. Specific Cytochrome P450 Isozymes.- I. Structural Studies.- II. Enzymatic Studies.- 1. Hepatic.- 2. Extrahepatic.- III. Molecular Studies.- D. Induction.- E. Conclusions.- References.- 32 Regulation of Cytochrome P450 Expression.- A. Introduction.- B. Cytochrome P450 1 Family.- I. cis-Acting Regulatory Elements.- II. trans-Acting Regulatory Factors.- C. Cytochrome P450 2B Family.- D. Cytochrome P450 4A Family.- E. Conclusions.- References.- 33 Induction of Cytochromes P450 1 and P450 2 by Xenobiotics.- A. Introduction.- B. Historical Perspectives.- C. Induction of CYP1A1.- I. Need for New Protein Synthesis.- II. 2,3,7,8-Tetrachlorodibenzo-p-dioxin, Polycyclic Hydrocarbons and Cytochrome P450.- 1. TCDD Receptor or Ah Receptor.- 2. Polycyclic Hydrocarbon-Binding Protein or 4S Protein.- D. CYP1A1 and CYP1A2 Genes.- I. Induction of the Cytochrome P450 1 Subfamily by Polycyclic Hydrocarbons and Dioxins.- II. Regulation of the CYP1A1 Gene.- 1. Regulation by Polycyclic Hydrocarbons.- III. Further Notes on the Regulation of CYP1A2.- E. Cytochrome P450 2 Family.- I. CYP2B1 and CYP2B2.- 1. Cytochrome P450 2B Genes and Transcription.- 2. Phenobarbital Induction of Cytochrome P450 in Bacillus megaterium.- 3. Mechanism of Action of Phenobarbital as an Inducer of CYP2B.- F. CYP2E1.- I. Regulation of CYP2E1.- G. Conclusion.- References.- Section V: Chemical Modification, Protein-Protein and Protein-Lipid Interaction.- 34 Protein-Protein Interactions.- A. Introduction.- B. Microsomal Cytochrome P450 Monooxygenases.- I. Cytochrome b5 Interactions.- II. NADPH-Cytochrome P450 Reductase Interactions.- III. Cytochrome P450 Interactions.- C. Effects of Ionic Strength.- D. Role of the Hydrophobic Membrane-Binding Domain.- E. Mitochondrial P450 Monooxygenases.- I. Adrenodoxin-Adrenodoxin Reductase Interactions.- II. Adrenodox