Buch, Englisch, Band 105, 739 Seiten, PB, Format (B × H): 155 mm x 235 mm, Gewicht: 1169 g
Buch, Englisch, Band 105, 739 Seiten, PB, Format (B × H): 155 mm x 235 mm, Gewicht: 1169 g
Reihe: Handbook of Experimental Pharmacology
ISBN: 978-3-642-77765-3
Verlag: Springer
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Research
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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-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-Hydroxylase Deficiency.- II. Corticosterone Methyloxidase II Deficiency.- III. Dexamethasone (or Glucocorticoid) Suppressible Hyperaldosteronism.- IV. Types of Mutations Observed in the CYP11B Genes.- E. Summary.- References.- 42 Cholesterol Side Chain Cleavage Cytochrome P450 (P450scc).- A. Introduction.- B. Mechanism of the Reaction.- C. Properties of Cytochrome P450scc.- D. Regulation of Activity.- E. Molecular Biology.- References.- 43 Cytochrome P450cl7: Regulation of Gene Expression and Enzyme Function at the Bifurcation in Steroid Hormone Synthesis.- A. Introduction.- B. Localization and Developmental Changes.- C. Structural Characteristics and Expression of the CYP17 Gene.- D. Assumptions About Cytochrome P450cl7 Protein Structure.- E. Specificity of Ligand Binding.- F. Intrinsic and Extrinsic Regulation of Catalytic Properties.- G. Cytochrome P450cl7 as Target for Suppression of Steroid Hormone Synthesis by Drugs.- H. The Problem of Cytochrome P450cl7 Downregulation: Role of Substrate and Oxygen.- I. Pathophysiological Aspects.- References.- 44 25-Hydroxy vitamin D-la-Hydroxylases: An Examination of Renal and Extrarenal Sources.- A. Introduction.- I. Structure of Vitamin D.- II. General Vitamin D Metabolism.- B. Renal 25-Hydroxyvitamin D-1?-Hydroxylase.- I. Metabolic Control.- II. Characterization, Isolation and Reconstitution.- III. Molecular Mechanism of Regulation.- C. Extrarenal 25-Hydroxyvitamin D-1?-Hydroxylase(s).- I. Localization in Tissues of Extrarenal Origin.- II. Biochemical Characteristics.- III. Metabolic Control.- References.- 45 Steroid 21-Hydroxylase.- A. Introduction.- B. Biochemistry.- C. Molecular Genetic Analysis.- D. Congenital Adrenal Hyperplasia Due to 21-Hydroxylase Deficiency.- I. Clinical Features.- II. Genetic Analysis.- 1. Salt-Wasting Form.- 2. Simple Virilizing Form.- 3. Nonclassic Form.- E. Regulation.- F. Additional Progesterone 21-Hydroxylase activities.- G. Summary.- References.- 46 Sterol 26-Hydroxylase.- A. Introduction.- B. Stereochemistry and Nomenclature of 26-Hydroxylation.- C. Functions of Sterol 26-Hydroxylase.- I. Bile Acid Biosynthesis.- II. Vitamin D3 Metabolism.- III. Formation and Role of 26-Hydroxy cholesterol in Metabolism.- D. Purification and Characterization of Mitochondrial Cytochrome P450 Active in 26-Hydroxylation.- I. Rabbit Mitochondrial Cytochrome P450.- II. Rat Mitochondrial Cytochrome P450.- III. Pig Mitochondrial Cytochrome P450.- IV. Human Mitochondrial Cytochrome P450 and Cerebrotendinous Xanthomatosis.- References.- 47 Nitric Oxide Synthase (NOS).- A. Introduction.- B. NOS Characteristics.- C. Characterization of the NOS as a Cytochrome P-450.- D. Mechanistic Implications.- E. Conclusion.- References.
