Main description:

This book provides a comprehensive, organized, and concise overview of xenobiotic metabolic enzymes and their health implications. The subjects addressed are broad in scope with an emphasis on recent advances in research on biochemical and biomedical aspects of these enzymes. The xenobiotics discussed include not just drugs, but also food, smoke, and other environmental chemicals.
The subjects covered in this work include: metabolic enzymes and their catalyzed reactions, reactive intermediates generated from metabolic activation, oxidative stress mediated by electrophilic reactive intermediates, bioactivation - mediated cellular and functional damages, activation of Nrf2 - ARE pathway, genetic variations affecting metabolic enzyme expression, enzyme polymorphisms affecting xenobiotic - mediated toxicity, induction of metabolic enzymes for health benefits, and a diversity of metabolic enzyme modulators.

Contents:

1. Overview

1.1. Xenobiotics that humans are exposed to

1.1.1. Foods and drug; 1.1.2. Smoke and other chemicals

1.2. Metabolisms of foreign compounds before excretion

1.2.1 Activation enzymes: functionalization; 1.2.2. Detoxification enzymes:

Conjugation; 1.2.3. Mechanism of enzyme actions

1.3. Potential toxicity of metabolic reactive intermediates

Components; 1.3.3. Cellular functional damages

1.4. Genetic and environment factors affecting xenobiotic metabolism

1.4.1. Genetic polymorphisms; 1.4.2. Environment and lifestyle

1.5. Defenses against oxidative stress mediated by foreign compounds

1.5.1. Modulation of metabolic enzymes for health benefits; 1.5.2. Inducers of

metabolic enzymes

2. Foreign Compounds: Foods, Drugs and Other Chemicals

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. , -unsaturated aldehydes; 2.1.6. Mycotoxin

2.2. Drugs

2.2.1. Acetaminophen; 2.2.2. Xanthine; 2.2.3. Terfenadine; 2.2.4. Menadione;

2.2.5. Diazepam

2.3. Household products

2.3.1. Benzene; 2.3.2. Phenol

2.4. Smoke

2.4.1. Nitrosamines; 2.4.2. Nicotine and benzo(a)pyrene

2.5. Environmental chemicals

2.5.1. Diesel exhausts; 2.5.2. Arsenic; 2.5.3. Polychlorinated biphenyls; 2.5.4. Dioxins

3. Absorption, Metabolism and Excretion of Foreign Compounds

3.1. Lipophiles versus hydrophiles

3.2. Sites of Action

3.3. Cell Membranes

3.4. Transport Mechanisms

3.4.1. Passive diffusion; 3.4.2. Facilitated diffusion; 3.4.3. Active transport

3.5. Metabolic Pathways

3.5.1. Activation metabolism; 3.5.2. Detoxification metabolism

3.6. Transport to external cell compartment

3.7. Metabolism precedes before excretion

3.8. Excretion

3.8.1. Renal excretion; 3.8.2. Reabsorption in the kidney; 3.8.3. Hepatic excretion;

3.8.4. Skin excretion

4. Metabolism of Foreign Compounds

4.1. Activation metabolism

4.1.1. Functionalization reactions; 4.1.2. Metabolic reactive intermediates

4.2. Detoxification metabolism

4.2.1. Conjugation reactions; 4.2.2. Non-conjugation reactions

4.3. Defenses against metabolites generated from bioactivation

4.3.1. Antioxidants; 4.3.2. Detoxifying enzymes

5. Bioactivation Metabolism: Activation Enzymes

5.1. Major activation enzymes

5.2. Oxidative enzymes

5.2.1. Cytochrome P450; 5.2.2. Flavin-Containing Monooxygenase;

5.2.3. Amine Oxidase; 5.2.4. Lipoxygenase; 5.2.5. Alcohol Dehydrogenase

5.2.6. Aldehyde Oxidase; 5.2.7. Xanthine Oxidase; 5.2.8. Peroxidase

5.2.9. Prostaglandin H synthase

5.3. Oxidation at specific atom or group

5.3.1. Oxidation at carbon atom; 5.3.2. Oxidation at nitrogen atom

5.3.3. Oxidation of unsaturated hydrocarbon

5.4. Reductive enzymes

5.4.1. Nitroreductase; 5.4.2. Azoreductase; 5.4.3. Aldo-keto reductase

5.5. Reduction at specific atom or group

5.5.1 Reduction at nitrogen; 5.5.2 Reduction of carbonyl group

5.6. Hydrolytic Enzymes

5.6.1. Carboxylesterase; 5.6.2 Epoxide Hydrolase

5.7. Hydrolysis at specific atom or group

5.7.1 Hydrolysis of ester; 5.7.2 Hydrolysis of amide

6. Functionalization Reactions Catalyzed by Activation Enzymes

6.1. Activation metabolism

6.1.1. Cytochrome P450; 6.1.2. Flavin monooxygenases; 6.1.3. Amine oxidases;

6.1.4. Nitroreductases; 6.1.5. Azoreductases; 6.1.6. Molybdenum hydroxylases;

6.1.7. Alcohol dehydrogenase; 6.1.8. Peroxidases; 6.1.9. Carboxylesterase

6.2. Oxidation reactions

6.2.1. Oxidation at carbon atom; 6.2.2. Oxidation at nitrogen atom;

6.2.3. Oxidation of unsaturated hydrocarbon

6.3. Reduction reactions

6.3.1. Reduction at nitrogen atom; 6.3.2. Reduction of carbonyl group

6.4. Hydrolysis reactions

6.4.1. Carboxylesterase; 6.4.2. Epoxide Hydrolase

7. Detoxifying Metabolism: Detoxification Enzymes

7.1. Excretors

7.2. Conjugation enzymes

7.2.1. Uridine-diphosphate-glucuronosyltransferases ; 7.2.2. Glutathione S-transferases;

7.2.3. Sulfotransferases; 7.2.4. N-acetyltransferases; 7.2.5. Methyltransferases;

7.2.6. Acyltransferases

7.3. Non-conjugation enzymes

7.3.1 Quinone reductase; 7.3.2. Epoxide hydrolases

8. Conjugation Reactions Catalyzed by Detoxification Enzymes

8.1. Detoxification reactions

8.1.1. Conjugation enzymes; 8.1.2. Non - conjugation enzymes

8.2. Conjugation reaction at specific atom or group

8.2.1. Conjugation at O atom; 8.2.2. Conjugation at N atom; 8.2.3. Conjugation at C

atom; 8.2.4. Conjugation at S atom; 8.2.5. Conjugation of carboxylic acid

9. Reactive Intermediates Generated from Bioactivation

9.1. Reactive intermediates

9.1.1. Reactive oxygen / nitrogen species; 9.1.2. Free radicals

9.1.3. Positively or neutral charged electrophilic compounds

9.2. Foreign compounds that form toxic reactive intermediates

9.2.1. Drugs; 9.2.2. Herbs and dietary supplements; 9.2.3. Other chemicals

9.3. Metabolic enzymes involved in reactive intermediate formation

9.3.1. Functionalization reactions; 9.3.2. Conjugation reactions

9.4. Oxidation reactions involved in reactive intermediate formation

9.4.1. Cytochrome P450 catalysis; 9.4.2. Peroxidase catalysis

9.5. Factors affecting reactive intermediate accumulation

9.6. Reactive intermediate interacting with proteins, DNA and lipids

9.6.1. Protein adducts; 9.6.2. DNA adducts; 9.6.3. Lipid peroxidation

10. Electrophilic Nature of Metabolic Reactive Intermediates

10.1. Reactive intermediates

10.2. Reactive oxygen species

10.3. Functional groups of electrophilic reactive intermediates

10.4. Cellular nucleophilic sites involving reactive intermediate binding

10.4.1. Protein; 10.4.2. DNA; 10.4.3. Lipid

10.5. Defenses against metabolic reactive intermediates

10.5.1. Detoxification enzymes; 10.5.2. Antioxidant enzymes; 10.5.3. Glutathione

10.5.4. Vitamins E and C and carotene

11. Oxidative Stress Mediated by Reactive Intermediates

11.1. Reactive chemical intermediates

11.1.1. Exogenous metabolites; 11.1.2. Endogenous metabolites

11.2. Reactive oxygen species (ROS)

11.2.1. ROS generated from mitochondria; 11.2.2. ROS generated from metabolic

bioactivation

11.3. Reactive nitrogen species

11.4. Oxidative stress mediated damages

11.5. Defense against oxidative stress

12. Xenobiotics Bioactivation - Mediated Cellular Damages

12.1. Exhibition of foreign compound toxicity

12.1.1. Natural toxicity; 12.1.2. Metabolic bioactivation; 12.1.3. Induced toxicity

12.2. Oxidative stress generated from metabolic reactive intermediates

12.3. Interactions with cellular components

12.3.1. Interactions with proteins; 12.3.2. Interactions with DNA; 12.3.3. Interactions

with lipids

12.4. Cellular functional damages

12.4.1. Mitochondrial function intervention; 12.4.2. Interactions with ion transporters

12.4.3. Interference with enzymatic functions; 12.4.4. Immune suppression and

stimulation effects; 12.4.5. Chemical carcinogenesis; 12.4.6. Age-related disorders

13. Nrf2/ARE Pathway Defense Against Oxidative Stress

13.1. Oxidative stress and biochemical dysregulation

13.2. Role of Nrf2 - ARE pathway

13.3. Nrf2 - Keap1-ARE pathway in the absence of oxidative stress

13.4. Nrf2-Keap1-ARE pathway in the presence of oxidative stress

13.5. Activation of Nrf2-ARE pathway

13.6. Nrf2 - ARE pathway on cytoprotection

13.6.1. Induction of detoxification enzymes; 13.6.2. Phytochemicals for cytoprotection

13.6.3. Dietary phytochemicals

14. Genetic Variations and Polymorphisms of Metabolic Enzymes

14.1. Genetic polymorphisms affecting metabolic enzymatic functions

14.2. Effects of enzyme polymorphism on xenobiotics - mediated toxicity

14.3. Polymorphisms of detoxification enzymes: transferases

14.3.1. Glutathione S-transferase polymorphism; 14.3.2. UDP-glucuronosyltransferase

polymorphism; 14.3.3. Sulfotrasferase polymorphism; 14.3.4. N-Acetyltransferase

polymorphism; 14.3.5. Methyltransferase polymorphism

14.4. Polymorphisms of detoxification enzymes: non-transferases

14.4.1. Quinone reductase and oxidoreductase polymorphisms; 14.4.2. Epoxide

hydrolase polymorphism

15. Enzyme Polymorphisms Affecting Xenobiotic Toxicity

15.1. Differential susceptibility to potentially xenobiotic toxicity

15.1.1. Susceptibility to drug toxicity; 15.1.2. Susceptibility to diverse toxicity

15.2. Enzyme polymorphisms affecting xenobiotic metabolisms

15.2.1. Cytochrome P450 (CYP450); 15.2.2. Alcohol dehydrogenase and aldehyde

dehydrogenase;15.2.3. Glutathione-S-transferase; 15.2.4. UDP-glucuronosyl

transferase

15.3. Species differences affecting foreign compound metabolisms

15.3.1. Susceptibility to aflatoxin toxicity in humans, but not in mice; 15.3.2.

Resistance to tamoxifen toxicity in humans, but not in rats; 15.3.3. 4-Ipomeanol

toxicity response to humans versus rodents

16. Inducibility of Foreign Compound Metabolic Enzymes

16.1. Inducibility of metabolic enzymes

16.2. Features of metabolic enzyme inducers

16.3. Monofunctional and bifunctional inducers

16.4. Inducer - enzyme interactions

16.4.1. Michael reaction acceptors; 16.4.2. Unsaturated carbon - carbon bonds;

16.4.3. Phenolic hydroxyl groups

16.5. Antioxidant response element

17. Induction of Enzymes for Health Benefits

17.1. Metabolic enzyme modulation

17.2. Activation enzyme modulation

17.3. Detoxification enzyme modulation

17.4. Balance between activation and detoxification

17.5. Enzyme modulation as a defense against potential toxic effects

17.6. Defense against xenobiotic toxicity

17.7. Mechanism of metabolic enzyme modulation

17.8. Lifestyle modulation of metabolic enzymes

17.8.1. Alcohol; 17.8.2. Cigarette smoke

18. Diversity of Metabolic Enzyme Modulators

18.1. Isothiocyanates

18.2. 1,2-dithiole-3-thione and its derivatives

18.3. Indole-3-carbinol

18.4. Polyphenols, flavonoids and isoflavones

18.5. Organosulfur compounds

18.6. Terpenes and terpenoids

18.7. Geniposide

19. Dietary Inducers of Detoxification Enzymes

19.1. Cruciferous vegetables

19.1.1. Sulfur - containing compounds; 19.1.2. Non-sulfur-containing compounds

19.2. Allium vegetables

19.2.1. Thiols; 19.2.2. Diallyl sulfides

19.3. Root vegetables

19.3.1. Flavonoids; 19.3.2. Carotenoids; 19.3.3. Curcumin

19.4. Fruits

19.4.1. Polyphenols; 19.4.2. Triterpenes;

19.5. Green tea and algae

19.5.1. Green tea; 19.5.2. Algae