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.
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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. Dis…