Metabolic Basis of Detoxication

Metabolic Basis of Detoxication: Metabolism of Functional Groups considers the possible fates of the relatively circumscribed number of functional groups that xenobiotics bear. An understanding of the possible reactions, and the chemical and biological factors influencing them, will contribute to the overall predictability of the fate of "real" molecules. This approach attempts to knit together the understanding of metabolic pathways with that of the enzymes that catalyze the specific steps.

The book contains 18 chapters and begins with a discussion of the biological oxidation of carbon atoms. This is followed by separate chapters on the metabolism of halogenated aliphatic hydrocarbons, aryl halides, heterocyclic rings, alcohols, aldehydes, and ketones. Subsequent chapters cover oxidative processes such as metabolic dealkylations and biological oxidation at nitrogen centers; the reduction of nitro and azo compounds and tertiary amine N-oxides; the oxidation, alkylation, acylation, and glycosylation of mercaptans; epoxide metabolism; and conjugation of phenols.

The book aims to inform and interest the pharmacologist and toxicologist concerning the biochemical aspects and to orient the biochemist to the pharmacological insights required in dealing with the metabolism of xenobiotics.

Contenu

Contributors

Preface

Introduction

Text

1. Oxidation of Foreign Compounds at Carbon Atoms

   I. Introduction

   II. Enzymes Involved in Foreign Compound Oxidation at Carbon Atoms

   III. Cytochrome P-450-Catalyzed Reactions

   IV. Examples of Oxidation Reactions at Carbon

   V. Factors That Affect the Rate and Site of Oxidation at Carbon

   References

2. Aliphatic Halogenated Hydrocarbons

   I. Introduction

   II. Chemistry of the Carbon-Halogen Bond

   III. Metabolic Reactions

   References

3. Aryl Halides

   I. Introduction

   II. Halogenated Benzenes

   III. Halogenated Biphenyls

   IV. Halogenated Naphthalenes

   V. Comments

   References

4. Oxidative Metabolism of Heterocyclic Ring Systems

   I. Introduction

   II. Nitrogen Heterocycles

   III. Sulfur Heterocycles

   IV. Oxygen Heterocycles

   References

5. Alcohols, Aldehydes, and Ketones

   I. Introduction

   II. Interconversion of Primary Alcohols and Aldehydes

   III. Oxidation of Aldehydes

   IV. Interconversion of Secondary Alcohols and Ketones

   V. Reduction of Ketones

   VI. Comments

   References

6. N-Dealkylation and Deamination

   I. Introduction and Definitions

   II. Chemical Reactions Leading to C- Bond Cleavages

   III. Enzymes Promoting C- Bond Cleavages

   IV. Distinctions between Alternative Mechanisms of Enzymatic C- Bond Cleavage

   V. Properties of Substrates for N-Dealkylation

   VI. Metabolic Significance and Pharmacological Consequences of N-Dealkylation

   References

7. Oxidation at Nitrogen Centers

   I. Introduction

   II. Chemical Aspects of Nitrogen Oxidation

   III. Biochemical Aspects of Nitrogen Oxidation

   IV. Enzyme Systems Involved in Metabolic Nitrogen Oxidation

   V. Role of Nitrogen Oxidation in the Detoxication and Toxication of Xenobiotics

   References

8. Reductive Metabolism of Nitrogen-Containing Functional Groups

   I. Introduction

   II. Reduction of Aromatic Nitro Groups

   III. Reduction of Azo Compounds

   IV. Tertiary Amine N-Oxide Reduction

   V. Factors Affecting Nitro, Azo, and TV-Oxide Reductions

   VI. Toxicological and Clinical Implications of the Biological Reduction of Organic Nitrogen

   References

9. Functional Groups Bearing Sulfur

   I. Introduction

   II. Biotransformation of Functional Groups Bearing Sulfur

   III. Identification of Toxic Metabolites

   References

10. Mercaptans

    I. Introduction

    II. Oxidation of Mercaptans

    III. Alkylation of Mercaptans

    IV. Acylation of Mercaptans

    V. Glycosylation of Mercaptans

    VI. Integrative Aspects of the Metabolism of Mercaptans

    References

11. Metabolism of Epoxides

    I. Introduction

    II. Chemistry of Epoxides

    III. In Vitro Epoxide Metabolism

    IV. Comments

    References

12. Hydrolysis of Carboxylic Esters and Amides

    I. Susceptibility of Carboxyl Esters and Amides to Hydrolysis

    II. Hydrolytic Detoxication of Esters and Amides In Vivo

    III. Hydrolytic Toxications and Bioactivations

    References

13. Conjugation of Phenols

    I. Chemistry of the Phenolic Hydroxy 1 Group

    II. Inventory of Substrates

    III. Factors Determining Conjugation In Vivo and in Isolated Cell Preparations

    IV. Inhibition of Conjugation In Vivo and in Isolated Cell Preparations

    References

14. Conjugation of Xenobiotic Carboxylic Acids

    I. Introduction

    II. The Carboxylic Acid Group

    III. Decarboxylation

    IV. Reduction

    V. Conjugation with Glucuronic Acid

    VI. Conjugations with Sugars

    VII. Conjugations with Amino Acids

    VIII. Methyl Ester Formation

    IX. Amide Formation

    X. Elimination Unchanged

    XI. Chemical and Biological Factors Governing the Relative Extents of Glucuronic Acid and Amino Acid Conjugations of an Acid

    XII. Consequences of the Conjugation of Carboxylic Acids

    References

15. Conjugation Reactions of Nitrogen Centers

    I. Carbamate Formation

    II. Acylation Reactions

    III. Sulfation at Nitrogen

    IV. Sugar Conjugations at Nitrogen

    V. N-Methylation

    VI. Concluding Remarks

    References

16. Metabolism of Organic Hydroperoxides

    I. Introduction

    II. Chemical and Physical Properties of Organic Hydroperoxides

    III. Enzymatic Basis for Organic Hydroperoxide Reduction

    IV. Antioxidants

    V. Assessment of Hydroperoxide Status in Metabolic Systems

    References

17. Role of the Intestinal Microflora

    I. Description of the Flora

    II. Some of the Detoxication Reactions of the Flora

    III. The Flora in Health and Disease

    IV. Comment

    References

18. Metabolism and Urinary Excretion

    I. Introduction

    II. Renal Function

    III. Examples of Interaction of Metabolism and Urinary Excretion

    IV. Comments

    References

Index