Activation and Detoxification Enzymes: Functions and Implications

✍ Scribed by Chang-Hwei Chen

• Publisher: Springer
• Year: 2024
• Tongue: English
• Leaves: 257
• Edition: 2
• Category: Library

✦ Synopsis

This book discusses the many advances in the understanding of the functions and implications of activation and detoxification enzymes. This organized, concise overview will meet the needs of those who are initially exposed to this important subject, particularly for students and researchers in the areas of biomedical sciences, biochemistry, nutrition, pharmacology, and chemistry. The book will also be valuable to advanced researchers. The book discusses subjects associated with foreign-compound-metabolizing enzymes with emphasis on biochemical aspects, including lipophilic foreign compounds, activation and detoxification enzymes, metabolic enzyme catalytic properties, reactive metabolic intermediates, biomedical and biochemical effects, genetic polymorphisms, enzyme inducibility, enzyme modulation for health benefits, dietary-related enzyme modulators, and structural characteristics of enzyme inducers. This new edition is updated throughout andfeatures completely new chapters on Oxidative and Electrophilic Stresses, Metabolite- Mediated Disease Conditions, and Defense Mechanism: Nrf2-ARE Pathway.

✦ Table of Contents

Preface
Introduction
Contents
1: Overview
1.1 Foreign Compounds That Humans Expose
1.2 Metabolic Reactions of Foreign Compounds
1.3 Activation Enzymes
1.4 Detoxification Enzymes
1.5 Reactive Metabolic intermediates
1.6 Oxidative Stress, Electrophiles, and Free Radicals
1.7 Lifestyle Modifications
1.8 Metabolic Intermediate-Induced Cell Toxicities
1.9 Genetic Polymorphism of Metabolic Enzymes
1.10 Defenses Against Metabolic Intermediates
1.10.1 Inducibility of Metabolic Enzymes
1.10.2 Diversified Classes of Enzyme Modulators
1.10.3 Induction and Inhibition Compound
1.11 Defense Mechanisms: Nrf2-ARE Pathway
1.12 Health Effects of Metabolic Intermediates
1.13 Induction of Metabolic Enzymes for Health Benefits
1.14 Dietary Effects on Metabolic Enzymes
Bibliography
2: Foreign Compounds: Foods, Drugs, Chemicals, and Lifestyles
2.1 Foods
2.1.1 Heterocyclic Amines
2.1.2 Nitrosamines
2.1.3 Polycyclic Aromatic Hydrocarbons
2.1.4 Azo Dyes
2.1.5 α,β-Unsaturated Aldehydes
2.1.6 Mycotoxin
2.2 Household Products
2.2.1 Benzene
2.2.2 Phenol
2.2.3 Phthalate
2.3 Pharmaceuticals
2.3.1 Acetaminophen
2.3.2 Xanthine
2.3.3 Terfenadine
2.3.4 Menadione
2.3.5 Diazepam
2.4 Environmental Chemicals
2.4.1 Diesel Exhausts
2.4.2 Arsenic
2.4.3 Polychlorinated Biphenyls
2.4.4 Dioxins
2.5 Lifestyles
2.5.1 Alcohol
2.5.2 Cigarette
Bibliography
3: Transport and Excretion of Foreign Compounds
3.1 Lipophiles Versus Hydrophiles
3.2 Hydrogen Bonding
3.3 Sites of Action
3.4 Cell Membranes
3.5 Transport Mechanisms
3.5.1 Passive Diffusion
3.5.2 Facilitated Diffusion
3.5.2.1 Transporter
3.5.2.2 Channel
3.5.3 Active Transport
3.5.3.1 Primary Active Transport
3.5.3.2 Secondary Active Transport
3.6 Metabolic Pathways
3.6.1 Phase I Activation Metabolism
3.6.2 Phase II Detoxification Metabolism
3.7 Transport to External Cell Compartment
3.8 Metabolism Precedes Excretion
3.9 Excretion of Foreign Compounds
3.9.1 Renal Excretion
3.9.2 Reabsorption in the Kidney
3.9.3 Hepatic Excretion
3.9.4 Skin Excretion
Bibliography
4: Metabolic Conversion of Foreign Compounds
4.1 Phase I Activation Metabolism
4.1.1 Oxidation Reactions
4.1.1.1 N-oxidation
4.1.1.2 S-oxidation
4.1.2 Hydroxylation Reactions
4.1.2.1 Aromatic Hydroxylation
4.1.2.2 Aliphatic Hydroxylation
4.1.3 Dealkylation Reactions
4.1.3.1 O-dealkylation
4.1.3.2 N-dealkylation
4.1.4 Hydrolysis
4.1.5 Epoxidation
4.2 Phase II Detoxification Metabolism
4.2.1 Conjugation Reactions
4.2.1.1 Glucuronide Conjugation
4.2.1.2 Glutathione Conjugation
4.2.1.3 Sulfonate Conjugation
4.2.1.4 Amino Acid Conjugation
4.2.1.5 N-acetyl Conjugation
4.2.1.6 Methyl Conjugation
4.2.2 Non-conjugation Reactions
4.2.2.1 Quinone Reductase Catalytic Reactions
4.2.2.2 Epoxide Hydrolase Catalytic Reactions
4.3 Toxification and Detoxification
4.3.1 Toxification Activation
4.3.2 Deactivation of Toxicity
4.3.3 Activation Versus Deactivation: Competing Pathways
Bibliography
5: Phase I Activation Enzymes
5.1 Activation of Foreign Compounds
5.2 Activation Enzymes
5.2.1 Oxidative Enzymes
5.2.2 Reductive Enzymes
5.2.3 Hydrolytic Enzymes
5.3 Catalytic Reactions
5.3.1 Oxidative Reactions
5.3.2 Reductive Reactions
5.3.3 Hydrolytic Reaction
Bibliography
6: Phase II Detoxification Enzymes
6.1 Exclusion of Foreign Compounds
6.2 Detoxification Enzymes
6.3 Conjugation Enzymes
6.3.1 Uridine-Diphosphate-Glucuronosyltransferase
6.3.2 Glutathione S-Transferase
6.3.3 Sulfotransferase
6.3.4 N-Acetyltransferase
6.3.5 Methyltransferase
6.3.6 Acyltransferase
6.4 Conjugation Enzyme-Catalyzed Reactions
6.4.1 Conjugation at O Atom
6.4.2 Conjugation at N Atom
6.4.3 Conjugation at C Atom
6.4.4 Conjugation at S Atom
6.4.5 Conjugation of Carboxylic Acid
6.4.6 Conjugation at OH Group
6.5 Non-conjugation Enzymes
6.5.1 Quinone Reductase
6.5.2 Epoxide Hydrolases
6.6 Non-conjugation Enzyme-Catalyzed Reactions
6.6.1 Quinone Reductase
6.6.2 Epoxide Hydrolase
Bibliography
7: Catalytic Reactions of Activation Enzymes
7.1 Cytochrome P450
7.1.1 Hydroxylation of Aliphatic or Aromatic Compounds
7.1.2 Epoxidation of Ether
7.1.3 Dehydrogenation of Alcohol or Aldehyde
7.1.4 Oxidation of N - or S - Compound
7.1.5 Dealkylation of Ether, Amide, or Carboxylic Acid
7.1.6 Oxidation of Carbon on Aromatic Ring
7.1.7 Activation of Benzo[a]pyrene
7.2 Prostaglandin H Synthase
7.3 Flavin Monooxygenase
7.4 Amine Oxidase
7.5 Nitroreductase
7.6 Azoreductase
7.7 Molybdenum Hydroxylase
7.8 Alcohol Dehydrogenase
7.9 Ribonucleotide Reductase
7.10 Peroxidase
7.11 Carboxylesterase
Bibliography
8: Catalytic Reactions of Detoxification Enzymes
8.1 Conjugation Reactions
8.1.1 Uridine Diphospho-Glucuronosyl Transferase
8.1.2 Glutathione S-Transferase
8.1.3 Sulfotransferase
8.1.4 Acyltransferase
8.1.5 N-Acetyltransferase
8.1.6 Methyltransferase
8.2 Non-conjugation Reactions
8.2.1 Quinone Reductase
8.2.2 Epoxide Hydrolase
8.3 Catalytic Actions on Atom or Molecule
8.3.1 Conjugation at O Atom
8.3.2 Conjugation at N Atom
8.3.3 Conjugation at C Atom
8.3.4 Conjugation at S Atom
8.3.5 Conjugation of Carboxylic Acid
8.4 Other Non-conjugation Reactions
Bibliography
9: Reactive Intermediates and Their Interactions
9.1 Reactive Intermediate Species
9.1.1 Reactive Oxygen Species
9.1.2 Reactive Nitrogen Species
9.2 Enzyme-Catalyzed Reactive Intermediate Formation
9.2.1 Mediation by Activation Enzymes
9.2.2 Mediation by Detoxification Enzymes
9.3 Interactions with Cellular Components
9.3.1 Protein Adducts
9.3.2 DNA Adducts
9.3.3 Lipid Peroxidation
9.4 Factors Affecting Foreign Compound Toxicity
9.5 Defense Against Reactive Intermediates
9.5.1 Conjugation Reactions
9.5.2 Glutathione
9.5.3 Antioxidant Enzymes
Bibliography
10: Metabolite-Associated Cell Toxicities
10.1 Intrinsic Toxicity
10.2 Reactive Intermediate-Related Toxicity
10.3 Lifestyle-Induced Toxicity
10.3.1 Alcohol
10.3.2 Cigarette
10.4 Toxic Effects on Cell Components
10.4.1 Protein Damage
10.4.2 DNA Damage
10.4.3 Lipid Peroxidation
10.5 Toxic Effects on Cellular Functions
10.5.1 Intervention with Mitochondria Functions
10.5.2 Interaction with Ion Transporters
10.5.3 Interference with Enzymatic Functions
10.5.4 Immune Suppression and Stimulation Effects
10.6 Chemical Carcinogenesis
10.7 Drug Metabolism Interference
Bibliography
11: Oxidative Stress: Reactive Chemical Intermediates
11.1 Oxidative Stress
11.1.1 Reactive Oxygen Species
11.1.2 Free Radicals
11.2 Reactive Intermediate-Mediated Oxidative Stress
11.2.1 Oxidative Stress on Biomolecules
11.2.2 Oxidative Stress and Inflammation on Diseases
11.3 Electrophilic Stress
11.3.1 Foreign Compound-Mediated Electrophiles
11.3.2 Varieties of Electrophiles
11.3.3 Electrophilic Stress on Biomolecules
11.3.4 Electrophiles on Disease Conditions
11.3.5 Electrophiles on Drug Metabolism
11.4 Defense Against Oxidative Stress
11.4.1 Chemoprevention Inducers
11.4.2 Nrf2- ARE Pathway
Bibliography
12: Metabolic Enzymes: Polymorphisms and Species Differences
12.1 Enzyme Polymorphisms on Xenobiotic Metabolism
12.2 Genetic Polymorphisms of Activation Enzymes
12.2.1 Cytochrome P450 (CYP450) Polymorphisms
12.2.2 Flavin-Containing Monooxygenase
12.2.3 Peroxidase
12.2.4 Carboxylesterase
12.2.5 Alcohol and Aldehyde Dehydrogenases Polymorphisms
12.3 Genetic Polymorphisms of Detoxification Enzymes
12.3.1 Glutathione S Transferase (GST)
12.3.2 UDP-Glucuronosyltransferase
12.3.3 Sulfotrasferase
12.3.4 N-Acetyltransferase
12.3.5 Methyltransferase
12.3.6 Quinone Oxidoreductase
12.3.7 Epoxide Hydrolase
12.4 Enzyme Polymorphisms on Alcohol and Smoke
12.4.1 Alcoholism
12.4.2 Smoker
12.5 Species Difference in Metabolic Enzyme Activities
12.5.1 Susceptibility to Aflatoxin Toxicity between Humans and Mice
12.5.2 Resistance to Tamoxifen Toxicity in Humans, Not in Rats
12.5.3 Different 4-Ipomeanol Toxicity Between Humans and Rodents
Bibliography
13: Defense Against Oxidative Stress: Nrf2-ARE Pathway
13.1 Transcription Factor Nrf2
13.1.1 Role of Nrf2 on Oxidative Stress
13.1.2 Keap1 Regulation of Nrf2 Activity
13.2 Activation of Nrf2-ARE Pathway
13.3 Nrf2-KeapP1-ARE Pathway
13.4 Molecular Mechanism of Nrf2-ARE Pathway
13.4.1 In the Absence of Oxidative Stress
13.4.2 In the Presence of Oxidative Stress
13.5 Cytoprotection Through Nrf2-ARE Pathway
13.5.1 Induction of Nrf2 - ARE Pathway
13.5.2 Enzyme Inducers for Cytoprotection
13.5.3 Over-Activation of Nrf2-ARE Pathway
13.6 Role of Nrf2 in Diseases
13.7 Nrf2-Inducing Compounds for Chemoprevention
Bibliography
14: Inducibility of Metabolizing Enzymes
14.1 Inducibility of Activation Enzymes
14.2 Inducibility of Detoxification Enzymes
14.3 Lifestyle Modification
14.4 Monofunctional and Bifunctional Inducers
14.5 Balance Between Activation and Detoxification Metabolisms
14.6 Enzyme Modulation Against Potential Toxicity
14.6.1 Enzyme Modulation
14.6.2 Hypothesis of Detoxification Enzyme Induction
14.7 Inducer-Metabolic Enzyme Interactions
14.7.1 Michael Reaction Acceptors
14.7.2 Unsaturated Carbon-Carbon Bonds
14.7.3 Phenolic Hydroxyl Groups
Bibliography
15: Inducibility of Metabolizing Enzymes
15.1 Defense Against Potential Metabolic Toxicity
15.1.1 Modification of Activation Enzymes
15.1.2 Modification of Detoxification Enzymes
15.1.3 Antioxidant Activities
15.2 Modification of Metabolic Enzymes
15.2.1 Modification of Activation Enzymes
15.2.2 Modulation of Detoxification Enzymes
15.3 Major Inducers of Metabolic Enzymes
15.3.1 Sulforaphane and Other Isothiocyanates
15.3.2 1,2-Dithiole-3-Thione and Derivatives
15.3.3 Indole-3-Carbinol
15.3.4 Flavonoids and Isoflavones
15.3.5 Polyphenols
15.3.6 Organosulfur Compounds
15.3.7 Terpenes and Terpenoids
15.4 Other Inducers
15.4.1 Phenobarbital
15.4.2 Grapefruit
Bibliography
16: Diversified Classes of Enzyme Modulators
16.1 Substrate-Enzyme Interactions
16.1.1 Electrophilic and Nucleophilic Groups
16.1.2 Conjugation of Metabolite
16.2 Interaction of Modulator with Metabolic Enzyme
16.2.1 Enzyme-Substrate Interaction
16.2.2 Enzyme Conformation
16.3 Michael Acceptor Functionalities
16.4 Enzyme Modulators with Michael Acceptor Characteristics
16.5 Diversities of Enzyme Inducers
16.5.1 Ortho-Hydroxyl Group on Aromatic Ring
16.5.2 Chemical Structures of Enzyme Inducers
Bibliography
17: Metabolite-Associated Disease Conditions
17.1 Metabolite-Associated Hepatotoxicity
17.1.1 Alcohol and Aldehyde
17.1.2 Aflatoxin-Induced Hepatic Carcinogenesis
17.1.3 Acetaminophen-Induced Hepatocyte Injury
17.1.4 Other Factors
17.2 Metabolic Intermediate-Associated Kidney Toxicities
17.3 Metabolite-Associated Cancer and Other Toxicities
17.3.1 Cancer
17.3.2 Neurodegeneration
17.3.3 Cataract
17.4 Drug Efficacy and Adverse Responses
17.4.1 Drug Efficacy
17.4.2 Drug Adverse Responses
17.5 Chemoprevention Against Toxicities
17.5.1 Toxic Metabolites
17.5.2 Chemoprevention
17.5.3 Induction of Detoxification Enzymes
17.5.4 Nrf2- Keap1 Pathway
Bibliography
18: Metabolic Enzyme Induction for Health Benefits
18.1 Metabolic Enzyme Modulation
18.1.1 Activation Enzyme Modulation
18.1.2 Detoxification Enzyme Modulation
18.1.3 Balance Between Activation and Detoxification Inductions
18.2 Varieties of Metabolic Enzyme Inducers
18.2.1 Activation Enzyme Inducers
18.2.2 Detoxification Enzyme Inducers
18.3 Monofunctional and Bifunctional Inducers
18.3.1 Monofunctional Inducers
18.3.2 Bifunctional Inducers
18.4 Inducer-Drug Interactions
Bibliography
19: Diet Effects on Metabolic Enzymes
19.1 Dietary Modulation of Metabolic Enzymes
19.1.1 Vegetables
19.1.2 Cruciferous Vegetables
19.1.3 Allium Vegetables
19.1.4 Root Vegetables
19.2 Fruits
19.2.1 Polyphenols
19.2.2 Eriodyctiol and Quercetin
19.2.3 Kaempferol and Pomegranate
19.2.4 Anthocyanin and Procyanidin
19.2.5 Triterpenes
19.3 Herbs
19.3.1 Ginseng
19.3.2 Herb-Drug Interaction
19.4 Beverage
19.4.1 Epigallocatechin-3-Gallate
19.4.2 Polyphenols
19.5 Alcohol
19.5.1 Acetaldehyde
19.5.2 Curcumin Protective Effect
19.6 Algae
19.6.1 Chlorophyll
19.6.2 Unsaturated Fatty Acid
19.6.3 Polysaccharide
19.7 Dietary Inducer-Drug Interactions
19.7.1 Grapefruit
19.7.2 Sulforaphane
19.7.3 Curcumin
Bibliography
Index