Biological Basis of Detoxication

Biological Basis of Detoxication focuses on the biological processes involved in detoxication, with emphasis on the biochemistry of the removal of xenobiotics from an organism. Topics range from the formation of toxic metabolites and compounds that are not metabolized at all to the tissue distribution and nutritional considerations, the kinetics and mechanisms of the metabolic and excretory processes, and the integration of xenobiotic metabolism in the activation and detoxication of carcinogens.
Organized into 14 chapters, this book begins with an overview of the enzymatic basis for the metabolic activation of foreign compounds in forming reactive chemical intermediates. The first few chapters discuss the identification of reactive electrophiles derived from xenobiotics, intratissue distribution of activating and detoxicating enzymes, enzymatic and non-enzymatic modes of xenobiotic metabolism, and unmetabolized compounds. The middle chapters explore the biological basis of detoxication of oxygen free radicals, physiologic and kinetic aspects of the fate of xenobiotics, excretion of xenobiotics, and effects of nutrition on detoxication. The remaining chapters look at the relationships between the enzymes of detoxication and host defense mechanisms, metabolic basis of target organ toxicity, the enzymatic factor in selective toxicity, and intraindividual and interindividual variations in rates of hepatic metabolism of exogenous chemicals.
Pharmacologists, toxicologists, and biochemists will find this book highly informative.

Contenu

Contributors
Preface

1. Metabolic Formation of Toxic Metabolites
   I. Introduction
   II. General Examples of Metabolic Activation
   III. Specific Examples of Metabolic Activation
   IV. Comments
   References
2. Integration of Xenobiotic Metabolism in Carcinogen Activation
   and Detoxication
   I. Introduction
   II. Identification of Reactive Electrophiles Derived from Xenobiotics
   III. Cell Specificity of Xenobiotic Effects
   IV. Classification of Xenobiotic Activation Pathways
   V. Partition of Metabolic Pathways
   VI. Regioselectivity and Stereoselectivity of Cytochrome P-450
   VII. Epoxide Hydrolase
   VIII. Absolute Monooxygenase Activity in the Activation Pathway
   IX. Cellular Cosubstrates of Xenobiotic Metabolism
   X. UDPglucuronyltransferases and Sulfotransferases
   XI. Glutathione S-Transferases
   XII. Inhibitors of Cellular Transferase Activity
   XIII. Xenobiotic Metabolism in the Nuclear Envelope
   XIV. Transport of Reactive Intermediates and Precursors
   XV. Comments
   References
   3.Ontogenesis
   I. Introduction
   II. Developmental Profiles of Drug-Metabolizing Enzymes
   III. Factors Influencing Drug-Metabolizing Enzyme Development
   IV. Comments: The Biological and Clinical Consequences of Drug-Metabolizing Enzyme Ontogenesis
   References
   4.Intratissue Distribution of Activating and Detoxicating Enzymes
   I. Introduction
   II. Distribution within the Liver
   III. Distribution within the Lung
   IV. Distribution within the Skin
   V. Comments
   References
   5.Nonenzymatic Biotransformation
   I. Introduction
   II. Reactions with Macromolecules as Borderline Cases
   III. Reactions with Endogenous Nucleophiles
   IV. Reactions with Endogenous Electrophiles
   V. Breakdown and Rearrangement Reactions of Xenobiotics and Prodrugs in Acidic and Neutral Aqueous Media
   VI. Reactions between Two Xenobiotics
   VII. Comments
   References
3. Unmetabolized Compounds
   I. Introduction
   II. Criteria for Classification of a Foreign Compound as Being Unmetabolized
   III. Properties of Unmetabolized Compounds
   IV. Toxicological Implications
   V. Comments
   References
   7.Biological Basis of Detoxication of Oxygen Free Radicals
   I. Introduction
   II. Oxygen Free Radicals
   III. Defense Mechanisms: Enzymatic and Nonenzymatic
   IV. Factors Influencing Defense Mechanisms and the Production of Oxygen Free Radicals
   V. Biological Systems Associated with Increased Oxygen Free Radical Production
   VI. Comments
   References
4. Fate of Xenobiotics: Physiologic and Kinetic Considerations
   I. Introduction
   II. The Xenobiotic
   III. Hemodynamics
   IV. Xenobiotic Metabolism
   V. Xenobiotic Excretion
   VI. Eliminating Organs
   VII. Comments
   References
5. Excretion Mechanisms
   I. Introduction
   II. Renal Handling of Organic Anions and Cations
   III. Biliary Excretion of Xenobiotics
   IV. Salivary Excretion
   V. Excretion into Milk
   VI. Excretion into Expired Air
   VII. Comments
   References
6. Impact of Nutrition on Detoxication
   I. Introduction
   II. Fasting/Starvation
   III. Protein
   IV. Carbohydrate
   V. Lipid
   VI. Trace Nutrients-Vitamins and Minerals
   VII. Comments
   References
7. Relationships between the Enzymes of Detoxication and Host Defense Mechanisms
   I. Introduction
   II. Nonspecific Immunostimulants
   III. Adjuvant-Induced Arthritis
   IV. Reticuloendothelial System
   V. Interferon
   VI. Infection in Animals
   VII. Viral Infection in Humans
   References
8. Metabolic Basis of Target Organ Toxicity
   I. Introduction
   II. Distribution of the Toxin as a Factor in Target Organ Toxicity
   III. Role of Metabolism in Determining Target Organ Toxicity
   IV. Role of Specific Function of the Tissue
   V. Comments
   References
9. Enzymes in Selective Toxicity
   I. Introduction
   II. The Toxicological Significance of Enzymatic Conversion
   III. The Enzymatic Factor in Selective Toxicity
   IV. The Enzymatic Factor in Resistance
   V. Comments
   References
10. Intraindividual and Interindividual Variations
    I. Introduction
    II. Sources of Intraindividual Variability
    III. Sources of Interindividual Variability
    References
    Index