VOLUME I. Preface. List of Contributors. Abbreviations. Part One Endogenous Toxins Associated with Excessive Sugar, Fat, Meat, or Alcohol Consumption. Sub-Part Chemistry and Biochemistry. 1 Endogenous DNA Damage (Erin G. Prestwich and Peter C. Dedon). 1.1 Introduction. 1.2 Oxidatively Damaged DNA. 1.3 DNA Alkylation by Endogenous Electrophiles. 1.4 DNA and RNA Deamination. 1.5 Summary. References. 2 Modification of Cysteine Residues in Protein by Endogenous Oxidants and Electrophiles (Norma Frizzell and John W. Baynes). 2.1 Introduction. 2.2 Autoxidation of Cysteine. 2.3 Glutathione. 2.4 Lipoxidation. 2.5 Maillard Reactions of Cysteine. 2.6 Succination. 2.7 Conclusion. Acknowledgment. References. 3 Endogenous Macromolecule Radicals (Arno G. Siraki and Marilyn Ehrenshaft). 3.1 Introduction. 3.2 What is a Free Radical? 3.3 Free Radicals as Initiators of Macromolecule Damage. 3.4 Macromolecule Radical Formation Induced by Small Molecule Free Radicals. 3.5 Examples and Potential Application of Immuno-Spin Trapping (IST) for the Detection of Macromolecule Radicals. 3.6 Immunological Detection of Oxidized Tryptophan Residues in Proteins. References. 4 Alcohol-Derived Bioadducts (Geoffrey M. Thiele and Lynell W. Klassen). 4.1 Introduction. 4.2 The Generation of Reactive Metabolites. 4.3 Ethanol Metabolites React with Proteins. 4.4 Acetaldehyde Adducts. 4.5 Malondialdehyde. 4.6 Malondialdehyde-Acetaldehyde (MAA) Adducts. 4.7 4-Hydroxyalkenals. 4.8 Free Radical-Derived Adducts. 4.9 5-Deoxy-D-xylulose-1-phosphate (DXP). 4.10 Acetaldehyde-Glucose Amadori Product Adduct. 4.11 Immune Responses to Proteins Modified with Alcohol Metabolites. 4.12 The Role of Alcohol-Derived Bioadducts in Alcohol-Related Tissue Injury. 4.13 Future Directions. Acknowledgments. References. 5 Iron from Meat Produces Endogenous Procarcinogenic Peroxides (Denis E. Corpet, Francoise Gueraud, and Peter J. O'Brien). 5.1 Introduction. 5.2 Toxic Effects of Iron: Molecular Mechanisms. 5.3 Procarcinogenic Effects of Iron: In vitro Studies. 5.4 Procarcinogenic Effects of Iron in the Gut. 5.5 Procarcinogenic Effects of Iron Inside the Body. 5.6 General Conclusion. References. Sub-Part Molecular Toxicology Mechanisms of Dietary Endogenous Toxins. 6 Short Chain Sugars as Endogenous Toxins (Ludmil T. Benov). 6.1 Definition and Properties. 6.2 Short Chain Sugars and Reactive Oxygen Species. 6.3 Dicarbonyls. 6.4 Direct Reactions with Biomolecules. 6.5 Short Chain Sugars and Their Sources. 6.6 Glyceraldehyde 3-phosphate Dehydrogenase. 6.7 Triosephosphate Isomerase. Acknowledgment. References. 7 Fructose-Derived Endogenous Toxins (Peter J. O'Brien, Cynthia Y. Feng, Owen Lee, Q. Dong, Rhea Mehta, Jeff Bruce, and W. Robert Bruce). 7.1 Introduction. 7.2 Recent Increased Consumption of Fructose. 7.3 Health Concerns Associated with High Chronic Consumption of Fructose. 7.4 Sugars as a Source of Endogenous Reactive Carbonyl Formation and AGEs. 7.5 Rat Hepatocyte Studies on Endogenous Toxins Formed by Fructose Metabolism and/or Oxidation. 7.6 Cancer Risk and Genotoxicity of Fructose or Carbonyl Metabolites. 7.7 Disease Prevention by Fruits and Vegetables versus Fructose Concern. 7.8 Conclusions. References. 8 Glyceraldehyde-Related Reaction Products (Teruyuki Usui, Hirohito Watanabe, and Fumitaka Hayase). 8.1 Maillard Reaction. 8.2 Maillard-Related Diseases. 8.3 Glyceraldehyde-Modified Protein. 8.4 Glyceraldehyde-Derived AGEs. 8.5 Cytotoxicity and Oxidative Stress. References. 9 Estrogens as Endogenous Toxins (Jason Matthews). 9.1 Introduction. 9.2 Estrogen Synthesis. 9.3 Receptor-Mediated Estrogen Signaling. 9.4 DNA Damage Induced by Estrogen. 9.5 Oxidative Metabolism of Estrogen. 9.6 Role for Estrogen Receptor in ROS Generations. 9.7 Treatment of Estrogen-Dependent Diseases. 9.8 Conclusions. References. 10 Reactive Oxygen Species, Hypohalites, and Reactive Nitrogen Species in Liver Pathophysiology (Hartmut Jaeschke). 10.1 Introduction. 10.2 Reactive Oxygen Species. 10.3 Reactive Nitrogen Species. 10.4 Hypohalites. 10.5 Summary. References. Part Two Genetics: Endogenous Toxins Associated with Inborn Errors of Metabolism. 11 Oxalate and Primary Hyperoxaluria (Christopher J. Danpure). 11.1 Oxalate as an Endogenous Toxin. 11.2 Hereditary Oxalate Overproduction - The Primary Hyperoxalurias. 11.3 Cytotoxicity of Oxalate, Calcium Oxalate, and Related Metabolites. 11.4 Conclusions. References. 12 Pathophysiology of Endogenous Toxins and Their Relation to Inborn Errors of Metabolism and Drug-Mediated Toxicities (Vangala Subrahmanyam). 12.1 Introduction. 12.2 Pathophysiology of Hepatobiliary System. 12.3 Inborn Errors of Bile Acid/Salt Transporter Deficiencies. 12.4 Drugs and Cholestatic Liver Disease. 12.5 Phospholipases and Phospholipidosis. 12.6 Mechanisms of Toxicity Associated with Accumulated Metabolites during Inborn Errors of Metabolism. 12.7 Pathophysiology of Phenylketonuria and Hyperphenylalaninemia. 12.8 Conclusions. References. 13 Mechanisms of Toxicity in Fatty Acid Oxidation Disorders (J. Daniel Sharer). 13.1 Introduction. 13.2 Mitochondrial beta-Oxidation. 13.3 Peroxisomal Fatty Acid Oxidation. 13.4 Conclusions. Acknowledgments. References. 14 Homocysteine as an Endogenous Toxin in Cardiovascular Disease (Sana Basseri, Jennifer Caldwell, Shantanu Sengupta, Arun Kumar, and Richard C. Austin). 14.1 Cardiovascular Disease Risk. 14.2 Overview of Atherosclerosis. 14.3 Homocysteine Metabolism. 14.4 Hyperhomocysteinemia and CVD. 14.5 Genetic Causes of Hyperhomocysteinemia. 14.6 Recent Studies. 14.7 Potential Mechanisms through which Hyperhomocysteinemia Contributes to Atherogenesis. 14.8 Conclusions. References. 15 Uric Acid Alterations in Cardiometabolic Disorders and Gout (Renato Ippolito, Ferruccio Galletti, and Pasquale Strazzullo). 15.1 Introduction. 15.2 Dual Properties of Uric Acid as Antioxidant or Pro-Oxidant Molecule. 15.3 Effects of Uric Acid on the Arterial Wall Properties and Endothelial Function. 15.4 Causes of Hyperuricemia and Hypouricemia. 15.5 Hyperuricemia, Gout, and Their Treatment. 15.6 Uric Acid and Cardiovascular Disease. References. 16 Genetic Defects in Iron and Copper Trafficking (Douglas M. Templeton). 16.1 Introduction and Terminology. 16.2 Iron. 16.3 Copper. 16.4 Summary. References. 17 Polyglutamine Neuropathies: Animal Models to Molecular Mechanisms (Kelvin Hui and Jeffrey Henderson). 17.1 Neurobiology of Polyglutamine Diseases. 17.2 Animal Models of Polyglutamine Diseases. 17.3 Mechanisms of Polyglutamine-Induced Neural Injury. 17.4 Future Perspectives. Acknowledgments. References. VOLUME II. Abbreviations. Part Three Examples of Endogenous Toxins Associated with Acquired Diseases or Animal Disease Models. 18 Alcohol-Induced Hepatic Injury (Emanuele Albano). 18.1 Introduction. 18.2 Ethanol Metabolism and Toxicity. 18.3 Mechanisms of Alcohol Hepatotoxicity. 18.4 Conclusions. References. 19 Ethanol-Induced Endotoxemia and Tissue Injury (Radhakrishna K. Rao). 19.1 Alcoholic Endotoxemia. 19.2 Causes of Alcoholic Endotoxemia. 19.3 Influence of Alcoholic Endotoxemia on Different Organs. 19.4 Mechanism of Tissue Damage by Alcoholic Endotoxemia. 19.5 Factors that Ameliorate Alcoholic Endotoxemia and Tissue Damage. 19.6 Summary and Perspectives. Acknowledgments. References. 20 Gut Microbiota, Diet, Endotoxemia, and Diseases (Patrice D. Cani and Nathalie M. Delzenne). 20.1 Introduction. 20.2 Gut Microbiota and Energy Homeostasis. 20.3 Energy Harvest, Obesity, and Metabolic Disorders: Paradoxes? 20.4 Role of the Gut Microbiota in the Inflammatory Associated with Obesity. 20.5 Metabolic Endotoxemia and High-Fat Feeding: Human Evidence. 20.6 Conclusion. References. 21 Nutrient-Derived Endogenous Toxins in the Pathogenesis of Type 2 Diabetes at the beta-Cell Level (Christine Tang, Andrei I. Oprescu, and Adria Giacca). 21.1 Introduction. 21.2 Acute Effect of Glucose and FFA on Insulin Secretion. 21.3 Insulin Secretory Abnormalities in Type 2 Diabetic Patients. 21.4 beta-Cell Glucotoxicity. 21.5 beta-Cell Lipotoxicity. 21.6 Glucolipotoxicity. 21.7 Oxidative Stress as an Endogenous Toxin. 21.8 Oxidative Stress, beta-Cell Glucotoxicity, and Lipotoxicity. 21.9 Conclusion. References. 22 Endogenous Toxins and Susceptibility or Resistance to Diabetic Complications (Paul J. Beisswenger). 22.1 Introduction and Background. 22.2 Synthetic Pathways for Glycation Products. 22.3 Enzymatic Deglycation Pathways. 22.4 Susceptibility to Diabetic Complications Varies Widely among Individuals. 22.5 Overproduction of alpha-Dicarbonyls is Characteristic of Individuals Who are Prone to Diabetic Complications. 22.6 Oxidative Stress and Propensity to Diabetic Nephropathy. 22.7 Conclusions. References. 23 Serum Advanced Glycation End Products Associated with NASH and Other Liver Diseases (Hideyuki Hyogo, Sho-ichi Yamagishi, and Susumu Tazuma). 23.1 Introduction. 23.2 Formation Pathways of AGEs. 23.3 AGEs' Association in the Liver. 23.4 Circulating AGEs and Liver Disease. 23.5 Possible Molecular Mechanisms by which the AGEs-RAGE System is Involved in Liver Disease. 23.6 Conclusions. Acknowledgment. References. 24 Oxidative Stress in the Pathogenesis of Hepatitis C (Tom S. Chan and Marc Bilodeau). 24.1 Hepatitis C. 24.2 The Molecular Basis of Oxidative Stress in Hepatitis C. 24.3 The Emerging Role of Antioxidants in the Treatment of HCV. 24.4 Summary and Conclusions. References. 25 Oxidized Low Density Lipoprotein Cytotoxicity and Vascular Disease (Steven P. Gieseg, Elizabeth Crone, and Zunika Amit). 25.1 Introduction to Vascular Disease. 25.2 oxLDL Formation. 25.3 Toxicity of oxLDL. 25.4 Types of oxLDL. 25.5 Cell-Mediated Oxidation and Atherosclerotic Plaques. 25.6 Endogenous Antioxidants. 25.7 Mechanism of oxLDL Cytotoxicity. 25.8 Oxysterol and the Mitochondria. 25.9 Oxysterols and Calcium. 25.10 NADPH Oxidase and Apoptosis versus Necrosis. 25.11 The Future. References. 26 Oxidative Stress in Breast Cancer Carcinogenesis (Lisa J. Martin and Norman Boyd). 26.1 Introduction. 26.2 Markers of Oxidative Stress. 26.3 Oxidative Stress and Breast Cancer. 26.4 Oxidative Stress and Breast Cancer Risk Factors. 26.5 Mammographic Density (MD). 26.6 Association of Hormones, Mitogens, and Mutagens with Mammographic Density. 26.7 Potential Mechanisms for the Association of Mitogens and MDA with Mammographic Density and Breast Cancer Risk. 26.8 Summary. References. 27 Lifestyle, Endogenous Toxins, and Colorectal Cancer Risk (Gail McKeown-Eyssen, Jeff Bruce, Owen Lee, Peter J. O'Brien, and W. Robert Bruce). 27.1 Introduction. 27.2 Lifestyle Risk Factors for CRC. 27.3 Oxidative Stress Relates to Lifestyle and CRC Risk. 27.4 Energy Excess Relates Lifestyle and CRC Risk. 27.5 Interaction of Toxicity of Energy Excess and Oxidative Stress. 27.6 Future Research. References. 28 Dopamine-Derived Neurotoxicity and Parkinson's Disease (Jose Luis Labandeira-Garcia). 28.1 The Neurotransmitter Dopamine. 28.2 Dopaminergic Alterations - Parkinson's Disease. 28.3 Levodopa Therapy for PD and Progress of Dopaminergic Neuron Degeneration. 28.4 Dopamine Toxicity and Aging. 28.5 Dopamine Toxicity and Animal Models of Parkinsonism. 28.6 Mechanisms of Dopamine Neurotoxicity - Vesicular and Cytosolic Dopamine. 28.7 Neuromelanin Formation and Dopamine Toxicity. 28.8 Interaction between Dopamine Toxicity and Protein Aggregation. 28.9 Receptor-Dependent Dopamine Toxicity, Dopamine-Mediated Excitotoxicity, and Relevance for Huntington's Disease. 28.10 Dopamine and Neuroprotection. 28.11 Conclusion. Acknowledgments. References. 29 Dopamine Catabolism and Parkinson's Disease: Role of a Reactive Aldehyde Intermediate (Jonathan A. Doorn). 29.1 Dopamine Biosynthesis and Catabolism. 29.2 DOPAL as a Metabolite of DA: Importance to Pharmacology and Toxicology. 29.3 DOPAL Metabolism. 29.4 Mechanisms for Elevation in Levels of DOPAL. 29.5 DOPAL Toxicity. 29.6 DOPAL Reactivity with Proteins. 29.7 Relevance of DOPAL to PD: Summary and "Big Picture". Acknowledgments. References. 30 Tetrahydropapaveroline, an Endogenous Dicatechol Isoquinoline Neurotoxin (Young-Joon Surh and Hyun-Jung Kim). 30.1 Introduction. 30.2 Biosynthesis of THP. 30.3 Neurotoxic Potential of THP. 30.4 Biochemical Mechanisms Underlying THP-Induced Neurotoxicity. 30.5 Cellular Protection against THP-Induced Injuries. 30.6 Concluding Remarks. References. 31 Chemically Induced Autoimmunity (Michael Schiraldi and Marc Monestier). 31.1 Introduction. 31.2 Human Disease. 31.3 Animal Models of Chemically Induced Autoimmunity. 31.4 Conclusion. References. 32 Endogenous Toxins Associated with Life Expectancy and Aging (Victoria Ayala, Jordi Boada, Jose Serrano, Manuel Portero-Otin, and Reinald Pamplona). 32.1 Introduction. 32.2 Metabolism(s). 32.3 The Rate of Generation of Damage Induced by Mitochondrial Free Radicals and Life Span. 32.4 Structural Components that are Highly Resistant to Oxidative Stress and Life Span. 32.5 Oxidative Stress, Aging, and Dietary Restriction. 32.6 Nutritional Considerations on Methionine: A Public Health Matter. Acknowledgments. References. Part Four Therapeutics Proposed for Decreasing Endogenous Toxins. 33 Therapeutic Potential for Decreasing the Endogenous Toxin Homocysteine: Clinical Trials (Wolfgang Herrmann and Rima Obeid). 33.1 Homocysteine Metabolism. 33.2 Physiological Determinants of Plasma Homocysteine Level. 33.3 Causes of Hyperhomocysteinemia. 33.4 The Role of Vitamin B12 (Cobalamin). 33.5 Folic Acid, Folate (Vitamin B9). 33.6 Vitamin B6. 33.7 Homocysteine (Hcy) as an Endogenous Toxin - Human and Experimental Studies. References. 34 Prevention of Oxidative Stress-Induced Diseases by Natural Dietary Compounds: The Mechanism of Actions (Tin Oo Khor, Ka-Lung Cheung, Avantika Barve, Harold L. Newmark, and Ah-Ng Tony Kong). 34.1 Introduction. 34.2 Cytoprotective Effect of Dietary Compounds: Antioxidant Effects. 34.3 Conclusion Remarks. 34.4 Tribute to Professor Harold L. Newmark. Acknowledgments. References. 35 Genotoxicity of Endogenous Estrogens (James S. Wright). 35.1 Introduction. 35.2 Estrogens and Women's Health. 35.3 Causes of Estrogen Genotoxicity. 35.4 Enzymatic Reactions that Affect Estrogen Genotoxicity. 35.5 Conclusions. Acknowledgment. References. 36 Design of Nutritional Interventions for the Control of Cellular Oxidation (Elizabeth P. Ryan and Henry J. Thompson). 36.1 Overview. 36.2 Antioxidant-Chronic Disease Conundrum Terms. 36.3 The Design of an Intervention. 36.4 Designing the Next Generation of Nutritional Interventions. 36.5 Overall Principles. 36.6 The Broader Perspective. 36.7 Summary. Acknowledgments. References. Appendix Questions for Discussion. 1 What are "endogenous toxins?". 2 Why consider "alcohol drinking" in a review of endogenous toxins? 3 What endogenous toxins are involved in the development of type 2 diabetes? 4 What endogenous sugar/fatty acid toxins are involved in the development of nonalcoholic steatohepatitis (NASH)? 5 Inflammation and oxidative stress are involved in many disease processes. Are these chronic diseases a direct result of oxidative stress or are they a result of even more reactive endogenous toxins formed with the interaction of oxidative stress with labile metabolites? 6 Endogenous toxins resulting from inborn errors of metabolism appear to be involved in an increasing number of diseases. Can dietary modification (supplements or deletions) reduce the levels of these toxins? 7 Do differences in endogenous toxins explain the differences in chronic disease incidence with time and across populations in the world? References. Index.