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Main description:
In-depth coverage of advances in molecular biology, indicating the importance of drug and xenobiotic conjugates as transport forms of biologically active compounds. Part One describes molecular events associated with the expression and regulation of transferases and hydrolases involved in Phase II drug conjugation and deconjugation. Part Two deals with the regulation of Phase II conjugation, while Part Three critically reviews the importance of drug conjugates in pharmacology and toxicology. An up-to-date source of information of broad interest to pharmacologists and toxicologists.
Contents:
Section I: Transferases and Hydrolases Involved in Phase II Conjugation-Deconjugation Reactions, Genetic Polymorphism and Regulation of Expression.- 1 The Uridine Diphosphate Glueuronosyltransferase Multigene Family: Function and Regulation With 7 Figures.- A. Introduction.- B. The Physiological Roles of Uridine Diphosphate Glucuronosyltransferases.- I. Endogenous Compound Metabolism.- II. Drug and Xenobiotic Conjugation.- III. Role of Glucuronidation in Olfaction and Glycolipid Biosynthesis.- C. Localisation of Uridine Diphosphate Glucuronosyltransferases.- I. Tissue Distribution.- II. Topology of Uridine Diphosphate Glucuronosyltransferases in the Endoplasmic Reticulum.- D. The Uridine Diphosphate Glueuronosyltransferase Multigene Family.- I. Elucidation of Uridine Diphosphate Glueuronosyltransferase Heterogeneity.- II. Primary Structure and Post-Translational Processing of Uridine Diphosphate Glucuronosyltransferases.- III. Substrate Specificity of Uridine Diphosphate Glueuronosyltransferase Isoforms.- 1. Rat Uridine Diphosphate Glueuronosyltransferase Isoforms.- 2. Human Uridine Diphosphate Glueuronosyltransferase Isoforms.- IV. Structure and Mapping of Uridine Diphosphate Glueuronosyltransferase Gene Loci.- E. Factors Affecting Uridine Diphosphate Glucuronosyltransferase Expression.- I. Ontogeny.- II. Induction by Xenobiotics.- III. Genetic Deficiencies.- 1. Deficiency of Androsterone Uridine Diphosphate Glueuronosyltransferase.- 2. The Gunn Rat.- 3. Crigler-Najjar Syndrome.- 4. Gilbert Syndrome.- F. Concluding Remarks.- References.- 2 Sulfotransferase Enzymes With 6 Figures.- A. Introduction.- B. Classification of Sulfotransferase Enzymes.- I. Introduction.- II. Human Sulfotransferase Enzyme Classification.- III. Rat Sulfotransferase Enzyme Classification.- IV. Molecular Classification of Sulfotransferase Enzymes.- C. Assays for Sulfotransferase Enzymes.- D. Purification of Sulfotransferase Enzymes.- E. Molecular Cloning of Sulfotransferase Enzyme cDNAs.- I. Introduction.- II. Phenol Sulfotransferase cDNAs.- III. Estrogen Sulfotransferase cDNAs.- IV. Hydroxysteroid Sulfotransferase cDNAs.- V. Flavonol Sulfotransferase cDNAs.- VI. Conclusions.- F. Properties of Sulfotransferase Enzymes.- I. Introduction.- II. Phenol Sulfotransferase Properties.- 1. Human Phenol Sulfotransferase Properties.- 2. Rat Phenol Sulfotransferase Properties.- 3. Properties of Phenol Sulfotransferase in Other Species.- III. Estrogen Sulfotransferase Properties.- IV. Hydroxysteroid Sulfotransferase Properties.- V. Flavonol Sulfotransferase Properties.- G. Regulation of Sulfotransferase Enzymes.- I. Introduction.- II. Sulfotransferase Enzyme Pharmacogenetics.- III. Humoral Regulation of Sulfotransferase Enzymes.- H. Conclusion.- References.- 3 Regulation of Expression of Rat Liver Glutathione S-Transferases: Xenobiotic and Antioxidant Induction of the Ya Subunit Gene With 6 Figures.- A. Perspectives.- B. Occurrence and Structure.- C. Nomenclature.- D. cDNA and Genomic Clones of Rat Glutathione S-Transferases.- I. cDNA Clones of the Alpha Gene Family (Subunits Yal, Ya2, and Yc).- II. cDNA Clones of the Mu Gene Family (Subunits Ybl, Yb2, Yb3, and Yb4).- III. cDNA Clones of the Pi Gene Family (Subunit Yp).- IV. cDNA Clones of the Theta Gene Family (Subunit Yrs).- V. cDNA Clones of the Microsomal Gene Family.- E. Structure of Glutathione S-Transferase Genes.- I. Glutathione S-Transferase Alpha Class Family.- II. Glutathione S-Transferase Mu Class Family.- III. Glutathione S-Transferase Pi Class Family.- F. Structure-Function Analysis of Glutathione S-Transferases.- I. Site-Directed Mutagenesis.- II. Crystallographic Solution of Glutathione S-Transferases.- G. Transcriptional Regulation of Glutathione S-Transferase Gene Expression.- I. Pi Gene (Subunit Yp).- II. Alpha Gene (Subunit Ya1).- 1. Identification of Regulatory Elements.- 2. Sequence Requirements of the Antioxidant-Responsive Element for Basal and Xenobiotically Inducible Activity.- 3. Induction of the Ya Subunit Gene by Phenolic Antioxidants Through the Antioxidant-Responsive Element.- 4. DNA Binding Studies.- H. Transcriptional Activation Through the Antioxidant and Xenobiotic-Responsive Element: A Study of Model Compounds.- I. Mechanisms of Induction of Glutathione S-Transferase Ya1 Subunit Gene.- References.- 4 Human N-Acetyltransferases With 3 Figures.- A. Introduction.- B. Biochemical and Immunochemical Studies on Liver Cytosolic N-Acetyltransferases.- C. Molecular Genetics of N-Acetyltransferases.- I. Identification of N-Acetyltransferase Genes.- 1. Cloning and Chromosomal Mapping.- 2. Heterologous Expression.- II. Properties of Hepatic and Recombinant N-Acetyltransferases.- 1. Substrate Selectivity.- 2. Stability.- D. The NAT 2 Locus.- I. Structural Heterogeneity.- 1. Coding Region Mutations.- 2. Far Downstream Mutations.- 3. Allelic and Genotypic Frequencies.- II. Characterization of Mutants.- 1. mRNA and Protein Content in Genotypically Defined Liver Tissue.- 2. Transfection of Mammalian Cells with NAT 2 Alleles and Chimeric Gene Constructs.- E. The NAT1 Locus.- I. Structural Heterogeneity.- 1. Allelic Variants of Caucasian NAT1.- 2. Ethnic Differences in Wild-Type NAT1.- II. Functional Aspects of Allelic Heterogeneity.- 1. Individual Variation in N-Acetylation of NAT1 Substrates In Vivo.- 2. Individual Variation in N-Acetylation of NAT1 Substrates In Vitro.- F. Independent Expression of NAT1 and NAT2.- References.- 5 Genetic Regulation of the Subcellular Localization and Expression of Glucuronidase With 5 Figures.- A. Introduction.- B. Endoplasmic Reticulum Glucuronidase.- I. Background.- II. Species Distribution of Liver Endoplasmic Reticulum Glucuronidase.- III. Organ and Cellular Distribution of the Endoplasmic Reticulum Glucuronidase-Egasyn Complex.- IV. Subcellular Distribution of the Complex.- 1. Background.- 2. Glucuronidase is Located Within the Lumen of the Endoplasmic Reticulum.- V. Lysosomal Glucuronidase was Associated with Egasyn During Subcellular Transit.- VI. Egasyn is an Esterase.- 1. Background.- 2. Identity of Egasyn Esterase.- VII. The Egasyn-Glucuronidase Interaction is Highly Specific.- VIII. The Esterase-Active Site of Egasyn is Involved in Complex Formation.- IX. The Propeptide Portion of the Glucuronidase Precursor is Involved in Complex Formation.- X. Sequence Similarity of the Glucuronidase Propeptide with Portions of the Reactive Site Region of the Serpin Superfamily.- XI. Endoplasmic Reticulum Retention Signal of Egasyn.- XII. Endoplasmic Reticulum Retention Signals of Other Esterases.- XIII. Is Complexation with Other Proteins a General Function of Endoplasmic Reticulum Esterases?.- XIV. Physiological Role of Endoplasmic Reticulum Glucuronidase.- XV. Physiological Role of Endoplasmic Reticulum Esterases.- XVI. Abnormal Subcellular Distribution of Glucuronidase in the Gusn Mouse.- C. Regulation of Expression of Glucuronidase.- I. Androgen-Regulated Genetic Elements.- II. Estrogen-Specific (Gus-e) Genetic Elements.- III. Tissue-Specific (Gus-u) and Temporal (Gus-t) Genetic Elements.- D. An Exoglucuronidase Acting on Nonsulfated Glycosaminoglycans.- E. Inherited ?-Glucuronidase Deficiency States.- I. Mucopolysaccharidosis VII in Humans.- II. Animal Models of Mucopolysaccharidosis VII.- References.- 6 Microsomal Amidases and Carboxylesterases With 5 Figures.- A. Introduction.- B. Distribution of Microsomal Amidases/Carboxylesterases.- C. Purification of Microsomal Amidases/Carboxylesterases from Different Species.- I. Rabbit.- II. Rat.- III. Mouse.- IV. Hamster.- V. Guinea pig.- VI. Dog.- VII. Human.- VIII. Monkey.- IX. Pig.- X. Cow.- D. Physical and Chemical Characteristics of Amidases/Carboxylesterases.- I. Amino Acid Compositions and Amino Acid Sequences.- II. Glycosylation Sites.- III. Active Sites.- IV. Antigenicities.- E. Catalytic Properties.- I. Catalytic Activities.- II. Reaction Mechanisms.- III. Enzyme Inhibition.- 1. Substrate Inhibition.- 2. Inactivation of Active Sites.- F. Regulation of Expression of Amidases/Carboxylesterases.- I. Regulation by Amidase/Carboxylesterase Genes.- II. Regulation by Hormones.- 1. Regulation by Sex Hormones.- 2. Regulation by Pituitary Hormones.- 3. Regulation by Pancreatic Hormones.- III. Enzyme Induction.- G. Role of Amidase/Carboxylesterase in Arylacetamide Toxicities and Carcinogenicities.- I. Toxicity of Phenacetin and Acetaminophen.- II. Carcinogenicity of Arylamines.- References.- 7 O-, N, and S-Methyltransferases With 2 Figures.- A. Introduction.- B. The Methyl Transfer Reaction.- C. S-Adenosyl-L-Methionine.- D. O-Methylation.- I. Overview.- II. Catechol O-Methyltransferase.- 1. Enzymology.- 2. Inhibitors.- 3. Role of Catechol O-Methyltransferase in the Therapy of Parkinson's Disease.- 4. Molecular and Structural Biology.- III. Hydroxyindole O-Methyltransferase.- 1. Enzymology.- 2. Molecular and Structural Biology.- E. N-Methylation.- I. Overview.- II. Phenethanolamine N-Methyltransferase.- 1. Enzymology.- 2. Molecular and Structural Biology.- III. Histamine N-Methyltransferase.- 1. Enzymology.- 2. Molecular and Structural Biology.- F. S-Methylation.- I. Overview.- II. S-Methyltransferases.- G. Pharmacogenetics of Methyltransferases.- H. Conclusion.- References.- Section II: Regulation of Phase II Conjugation: Deconjugation Reactions in Intact Cells and Tissues.- 8 Cofactor Supply as a Rate-Limiting Determinant of Hepatic Conjugation Reactions With 5 Figures.- A. Introduction.- I. Energy Requirements for Conjugation.- II. Metabolic Burden of Conjugation.- III. Drug Substrate Concentration as a Rate-Determining Factor for Conjugation Reactions.- B. Models Used to Study Regulation of Conjugation.- C. Glucuronidation.- I. Uridine Diphosphate Glucuronic Acid Metabolism.- II. Carbohydrate Supplies.- 1. Glycogen Levels.- 2. Endocrine Disorders and Glucuronidation.- III. Cellular Energetics and Glucuronidation.- 1. Hypoxia.- 2. Metabolic Inhibitors.- IV. The Cellular Oxidation-Reduction State and Glucuronidation.- V. Other Factors Influencing Glucuronidation.- 1. Volatile Anesthetics.- 2. Effects of Drugs and Other Chemicals.- VI. Intracellular Transport of Uridine Diphosphate Glucuronic Acid.- D. Sulfate Conjugation.- I. 3'-Phosphoadenosine-5'-Phosphosulfate Metabolism.- II. Availability of Inorganic Sulfate and Rates of Hepatic Sulfation.- III. Rate-Limiting Factors for Sulfate Conjugation.- IV. Cellular Energetics and Sulfation.- V. Other Metabolic Factors Affecting 3'-Phosphoadenosine-5'-Phosphosulfate Levels.- VI. Futile Cycling of Sulfate Conjugates.- E. Glutathione.- I. Glutathione Synthesis and Metabolism.- II. Mechanisms of Depletion of Hepatic Glutathione.- 1. Conjugation of Electrophilic Compounds.- 2. Oxidative Stress.- 3. Inhibition of Glutathione Synthesis.- 4. Fasting and Nutritional Influences.- 5. Hepatic Energetics.- 6. Other Factors Which Decrease Glutathione.- III. Methods of Increasing Hepatic Concentrations of Glutathione.- F. Other Pathways of Hepatic Conjugation.- References.- 9 Regulation of Drug Conjugate Production by Futile Cycling in Intact Cells With 4 Figures.- A. Introduction.- B. Properties of Hydrolases and Transferases Related to Futile Cycling of Conjugates.- C. Futile Cycling of Glucuronide Conjugates.- D. Futile Cycling of Sulfate Conjugates.- E. Conclusion.- References.- 10 Pharmacokinetic Modeling of Drug Conjugates With 22 Figures.- A. Introduction.- B. Hepatic Modeling: Tubular Flow Model.- I. Transmembrane Barrier.- II. Zonation of Enzymic Activities.- III. Nonlinear Protein Binding.- IV. Futile Cycling.- V. Flow.- VI. Cosubstrate.- C. Concluding Remarks.- References.- 11 Regulation of Drug Conjugate Processing by Hepatocellular Transport Systems With 1 Figure.- A. Introduction.- B. Transport Across the Basolateral Domain.- I. Transport from Plasma into the Hepatocyte.- 1. Na+-Taurocholate Cotransport - A Multispecific System.- 2. Na+-Independent Transport Systems.- II. Transport from Hepatocyte to Plasma.- C. Transport Across the Canalicular Domain.- I. Transport Systems from the Hepatocyte into Bile.- 1. P-Glycoprotein.- 2. Bile Acid Transport Systems.- 3. Nonbile Acid Organic Anion Transport Systems.- II. Transport from Bile into the Hepatocyte.- References.- Section III: Pharmacology and Toxicology of Drug Conjugates.- 12 Biologically Active Conjugates of Drugs and Toxic Chemicals With 5 Figures.- A. Introduction.- B. Biologically Active Drug Conjugates.- I. Morphine-6-Glucuronide.- II. Minoxidil Sulfate.- III. Other Drug Conjugates.- 1. Retinoid Glucuronides.- 2. Fatty Acid Conjugates.- 3. Acyl-Linked Glucuronides.- 4. Bile Acid Conjugates.- 5. Polymeric Conjugates.- C. Steroids.- I. Glucuronides.- II. Sulfates.- 1. Pregnenolone Sulfate.- 2. Dehydroepiandrosterone Sulfate.- D. Toxic Conjugates Formed and Released from Liver.- I. Poly cyclic Aromatic Hydrocarbons.- II. Glutathione Conjugates.- E. Activation of Drug Conjugates by Targeted Enzymes.- F. Conclusions.- References.- 13 Acyl Glucuronides as Chemically Reactive Intermediates With 10 Figures.- A. Acyl Glucuronides as Chemically Reactive Intermediates.- B. Intramolecular Rearrangements.- C. Nucleophilic Displacement.- D. Covalent Bonding to Biopolymers.- I. Albumin as Nucleophile.- II. Four Reagents and Three Mechanisms.- III. Product Stabilities.- E. Implications.- References.- 14 Roles of Uridine Diphosphate Glucuronosyltransferases in Chemical Carcinogenesis With 9 Figures.- A. Introduction.- I. Control of Nucleophilic Metabolites by Glucuronidation Preventing their Conversion to Electrophilic, Reactive Metabolites.- II. Initiation of Carcinogenesis by Reactive Metabolites.- III. Tumor Promotion and Reactive Metabolites.- B. Glucuronides as Transport Forms of Carcinogens.- I. Bladder Carcinogenesis.- II. Colon Carcinogenesis.- C. Role of Glucuronidation in Detoxication of Carcinogens.- I. Aromatic Hydrocarbons.- 1. Benzo(a)pyrene.- 2. Benzene.- 3. 2-Hydroxybiphenyl.- II. Aromatic Amines.- 1. 2-Acetylaminofluorene.- 2. Others.- D. Metabolism of Carcinogens by Isozymes of the Uridine Diphosphate Glucuronosyltransferase Enzyme Superfamily.- I. Factors Controlling Glucuronide Formation in the Intact Cell.- 1. The Uridine Diphosphate Glucuronic Acid Level.- 2. Localization of Uridine Diphosphate Glucuronosyltransferase: Latency.- 3. Interaction of Uridine Diphosphate Glucuronosyltransferases with Phospholipids.- 4. Sequestration of Substrates in the Microsomal Membrane.- II. Functions of Uridine Diphosphate Glucuronosyltransferase Isozymes.- 1. Uridine Diphosphate Glucuronosyltransferase Enzyme Superfamily.- 2. Substrate Specificity of Phenol Uridine Diphosphate Glucuronosyltransferases in Family 1A.- E. Regulation of Uridine Diphosphate Glucuronosyltransferase Isozymes.- I. General Features.- II. Regulation of Phenol Uridine Diphosphate Glucuronosyltransferase by the Ah Receptor.- III. Persistent Alterations of Phenol Uridine Diphosphate Glucuronosyltransferase in Preneoplastic Liver.- F. Conclusions.- References.- 15 Sulfonation in Chemical Carcinogenesis With 11 Figures.- A. Introduction.- B. Metabolic Activation of Chemical Carcinogens by Sulfonation.- I. Aromatic Amides and Amines.- 1. 2-Acetylaminofluorene.- 2. 4-Acetylaminobiphenyl.- 3. 4-Acetylaminostilbene.- 4. 2-Acetylaminophenanthrene.- 5. Phenacetin.- 6. 4-Aminoazobenzene, N-Methyl-4-Aminoazobenzene, and N,N- Dimethyl-4-Aminoazobenzene.- 7. Benzidine.- 8. Heterocyclic Aromatic Amines.- 9. Hydroxylamine-0-Sulfonic Acid.- II. Alkenylbenzenes.- 1. Safrole and Estragole.- 2. 1'-Hydroxy-2',3'-Dehyroestragole.- III. Polynuclear Aromatic Hydrocarbons.- 1. Methyl-Substituted Aromatic Hydrocarbons.- 2. Cyclopenta-Fused Aromatic Hydrocarbons.- 3. Phenols, Bay-Region Dihydrodiols, Tetraols of Polynuclear Aromatic Hydrocarbons.- IV. Nitrotoluenes.- V. ?-Hydroxynitrosamines.- VI. Miscellaneous Compounds.- 1. 3-Hydroxypurines.- 2. ?-Aminoalcohols.- 3. Hycanthone.- 4. Quercetin.- 5. 5-Hydroxymethylfurfural.- C. Concluding Remarks.- References.- 16 Glutathione Conjugate-Mediated Toxicities With 8 Figures.- A. Introduction.- B. Glutathione-Dependent Activation of Halogenated Alkanes and Alkenes.- I. Glutathione-Dependent Mutagenicity.- II. Cysteine Conjugate ?-Lyase-Dependent Mutagenicity.- III. Glutathione-Dependent Nephrotoxicity.- 1. The Role of Renal Transport.- 2. The Role of Renal Bioactivation.- 3. Mechanisms of Toxicity.- 4. The Role and Regulation of ?-Lyase.- C. Glutathione- and Quinone-Mediated Toxicities.- I. Biological (Re)activity of Quinone-Thioethers.- II. Enzyme Inhibition by Quinone-Thioethers.- III. Free Radical Formation by Quinone-Thioethers.- IV. Quinone-Thioether-Catalyzed Methemoglobinemia.- V. Quinone-Thioethers and Nephrotoxicity.- VI. Quinone-Thioethers and Neurotoxicity.- VII. Quinone-Thioethers and Alcoholism?.- VIII. ?-Glutamyl Transpeptidase and Quinone-Thioether-Mediated Toxicities.- D. Reversible Glutathione Conjugations and Their Toxicological Significance.- I. Isothiocyanates.- II. ?, ?-Unsaturated Aldehydes (Acrolein).- III. Isocyanates.- E. Pharmacologically Active Glutathione Conjugates.- I. Leukotrienes.- II. Nitric Oxide and Endothelium-Derived Relaxing Factor.- F. Summary.- References.- 17 Challenges and Directions for Future Research.- A. Introduction.- B. Search for Factors Regulating Polymorphic Expression of Phase II Conjugating and Deconjugating Enzymes.- I. Genetic Factors.- II. Environmental Factors.- C. Net Conjugate Production by Intact Cells.- I. Interaction Between Transferases and Hydrolases.- II. Cofactor Supply.- III. Transport of Conjugated Metabolites.- D. Mechanisms of Biologically Active Conjugates.- I. Chemically Active Toxic Conjugates.- 1. Sulfonates.- 2. Acyl Glucuronides.- 3. Glutathione Conjugates.- II. Pharmacologically Active Conjugates.- 1. Direct Acting Conjugates.- 2. Carrier Conjugates.- E. Conclusion.- References.
PRODUCT DETAILS
Publisher: Springer (Springer-Verlag Berlin and Heidelberg GmbH & Co. K)
Publication date: November, 2011
Pages: 560
Weight: 838g
Availability: Available
Subcategories: Biochemistry, Diseases and Disorders, Nuclear Medicine, Pharmacology
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