Caffeine : perspectives from recent research

Section I Metabolism and Kinetics. - I Products of Metabolism of Caffeine. - 1 Discovery and Chemical Structure of Methylxanthines. - 2 Formation of Uric Acid Metabolites. - 3 Introduction of Chromatographic Techniques. - 4 The Metabolic Studies by H.H. Cornish. - 5 Use of Labeled Methylxanthines. - 6 Metabolism of Theophylline in the Premature Infant. - 7 Metabolism of Labeled Theobromine and Identification of Uracil Derivatives. - 8 Use of Methyl-Labeled Caffeine in Breath Tests. - 9 Perinatal Caffeine and Theophylline Metabolism. - 10 Quantitative Metabolic Pathways of Dimethylxanthines. - 11 Identification of an Acetylated Uracil Metabolite in Man. - References. - II Measurement of Caffeine and Its Metabolites in Biological Fluids. - 1 Ultraviolet Spectrophotometry. - 2 Liquid Chromatography. - 3 Thin-Layer Chromatography. - 4 Immunoassays. - 5 Gas Chromatography - Mass Spectrometry. - 6 Carbon Dioxide Breath Test. - 7 Conclusions. - References. - III Interspecies Comparison of Caffeine Disposition. - 1 Absorption. - 2 Plasma Protein Binding. - 3 Distribution. - 4 Clearance. - 4.1 Renal Clearance. - 4.2 Metabolic Clearance. - 4.3 Urinary Metabolism. - 5 Kinetics of Primary Metabolites of Caffeine. - 6 Nonlinear Kinetics. - 7 Chronic Treatment in the Rat. - References. - Section II Intake. - IV Human Consumption of Caffeine. - 1 Introduction. - 2 Sources and Levels. - 2.1 Coffee. - 2.2 Tea. - 2.3 Cocoa and Chocolate Products. - 2.4 Soft Drinks. - 2.5 Drug Products. - 2.6 Standard Caffeine Content Values. - 3 Consumption Data Sources. - 4 Consumption Estimates. - 4.1 Market Research Corporation of America Survey. - 4.2 Market Facts Survey. - 4.3 Nationwide Food Consumption Survey. - 4.4 1982 Coffee Drinking Study. - 4.5 Standard Consumption Estimates. - 4.6 Consumption by Pregnant Women. - 5 Time Distribution of Caffeine Intake. - 6 Summary. - References. - Section III Physiological and Behavioral Effects. - V The Cardiovascular Effects of Caffeine. - 1 Introduction. - 2 Myocardial Contractility. - 3 Heart Rate. - 4 Blood Pressure. - 5 Clinical Pharmacology. - References. - VI Behavioral Effects of Caffeine. - 1 Introduction. - 2 Man. - 2.1 Performance in Laboratory Tests. - 2.2 Individual Variation. - 2.3 Effects in Children. - 2.4 Adverse Effects in Man. - 2.5 Comments on Studies of Behavioral Effects in Human Subjects. - 3 Experimental Animals. - 3.1 Mice. - 3.2 Rats. - 3.3 Other Species. - 4 Conclusions. - References. - Section IV Mechanisms of Effects. - VII Effects of Caffeine on Monoamine Neurotransmitters in the Central and Peripheral Nervous System. - 1 Introduction. - 2 Effects on Brain Monoamines. - 2.1 Serotonin. - 2.2 Catecholamines. - 3 Effects on Catecholamines in the Peripheral Nervous. - System. - References. - VIII Neuroendocrine Effects of Caffeine in Rat and Man. - 1 Introduction. - 2 Studies on Experimental Animals. - 3 Studies in Man. - 4 Conclusions. - References. - IX Adenosine as a Mediator of the Behavioral Effects of Xanthines. - 1 Physiologic Effects of Adenosine. - 2 Adenosine Receptor Localization. - 3 Adenosine Receptor Binding Properties. - 4 Behavioral Effects of Xanthines and Adenosine. - Derivatives. - References. - X Caffeine and the Cardiovascular Effects of Physiological Levels of Adenosine. - 1 Introduction: Caffeine as an Antagonist of Endogenous Adenosine. - 2 Effects of Circulating Adenosine. - 3 Implications of the Interaction of Caffeine with Endogenous Adenosine. - References. - Section V Direct Assessments of Effects on Health Editor of Section V: W. R. Grice. - XI Influence of Ingested Caffeine on Animal Reproduction. - 1 Introduction. - 2 Rats. - 2.1 Details of Experimental Reports. - 2.1.1 Caffeine in Drinking Solution. - 2.1.2 Caffeine in Feed. - 2.2 Summary and Conclusions. - 3 Mice. - 3.1 Details of Experimental Reports. - 3.1.1 Caffeine in Drinking Water. - 3.1.2 Caffeine Administered by Gavage. - 3.1.3 Caffeine Administered by Injection. - 3.2 Summary and Conclusions. - 4 Domestic Chickens. - 5 General Observations. - References. - XII The Teratogenic Potential of Caffeine in Laboratory Animals. - 1 Introduction. - 2 Results of Previous Animal Studies. - 2.1 Concordant Results. - 2.2 Discordant Results. - 3 Previous Reviews of Animal Studies. - 3.1 Federation of American Societies of Biology Report. - 3.2 Citizens' Petition to the Food and Drug Administration. - 3.3 Food and Drug Administration Review of Reproduction and Teratology Studies on Caffeine. - 3.4 National Soft Drink Association's Critique of the Collins Gavage Study. - 3.4.1 Procedural Criticisms. - 3.4.2 Maternal Toxicity. - 3.4.3 Skeletal Variants. - 3.4.4 No-Effect Levels. - 4 Remaining Unresolved Issues. - 4.1 Mechanism(s) of Teratogenic Action in Rodents. - 4.2 Skeletal Variants and Their Biological Significance. - 4.3 Interaction of Caffeine with Known Teratogens. - 4.4 Does Gavage in Animals Induce Complications Secondary to Emotional Stress? - 5 Summary and Conclusions. - References. - XIII Epidemiologic Studies of Birth Defects. - 1 What Is Epidemiology? - 2 Why the Need for Epidemiology? - 3 Limitations of Epidemiology. - 3.1 Associations, Not Causes. - 3.2 Quality of Data. - 3.2.1 Measures of Exposure. - 3.2.2 Outcome Data. - 3.2.3 Covariates. - 3.3 Biases. - 4 The Past. - 5 Recent Publications. - 5.1 Harvard Study. - 5.2 Boston University Study. - 5.3 Loma Linda Study. - 5.4 Yale Study. - 5.5 Overview. - 6 The Future. - References. - XIV The Carcinogenic Potential of Caffeine. - 1 Animal Studies. - 1.1 Published. - 1.2 Unpublished. - 1.3 Cited at Scientific Meetings and in Various Stages of Completion. - 1.4 General Conclusions. - 2 Chemical and Metabolic Studies. - 2.1 Metabolic Evidence. - 2.1.1 Direct Alkylation of DNA or Incorporation into DNA. - 2.1.2 Does Caffeine Undergo Metabolic Activation? - 2.1.3 Does Caffeine Undergo Covalent Binding? - 2.2 Structure-Activity Relationships. - 2.3 Associated Biological Activities of Caffeine. - 2.4 Nitrosation Reactions. - 2.5 Summary and Conclusions. - 3 Epidemiological Evidence. - 3.1 Cancer of the Urinary Bladder. - 3.2 Cancer of the Pancreas. - 3.3 Cancer of the Ovary. - 3.4 Conclusions. - 4 Summary of Evidence on Mutagenicity. - References. - XV The Mutagenic Potential of Caffeine. - 1 Introduction. - 2 Exposure. - 3 Results of Mutagenicity Tests. - 3.1 Gene Mutations. - 3.2 Chromosomal Aberrations. - 3.3 Caffeine in Combination with Other Agents. - 3.3.1 Micro-organisms. - 3.3.2 Drosophila melanogaster. - 3.3.3 Plants. - 3.3.4 Mammalian Cells in Culture. - 3.4 Summary and Risk Evaluation for Genetic Effects. - 4 Related Effects of Caffeine. - 4.1 Crossing-over. - 4.2 DNA Repair. - 4.3 Deoxyribonucleotide Pools. - 5 Conclusions. - References. - XVI Mechanism of Potentiation by Caffeine of Genotoxic Damage Induced by Physical and Chemical Agents: Possible Relevance to Carcinogenesis. - 1 Introduction. - 2 Enhancement by Caffeine of Toxicity and Chromosomal Damage Induced by Chemical Agents. - 3 Effects of Caffeine Alone on Normal DNA Replication. - 4 Effects of Genotoxic Agents on DNA Synthesis. - 5 Effects of Post-treatment with Caffeine on DNA Synthesis in Mammalian Cells Treated with Genotoxic Agents. - 6 Caffeine-Induced DNA Template Breakage in Treated Cells: Double-Strand Break Formation. - 7 Caffeine-Induced Premature Mitosis. - 8 Modifying Effects of Caffeine on Tumour Induction by Chemical and Physical Agents: Possible Role of DNA Repair. - 9 Conclusions. - References.