Biological Reactive Intermediates IV : Molecular and Cellular Effects and Their Impact on Human Health

The finding that chemicals can be metabolically activated to yield reactive chemical species capable of covalently binding to cellular macromolecules and the concept that these reactions could initiate toxicological and carcinogenic events stimulated a meeting by a small group of toxicologists at the University of Turku, in Finland, in 1975 (Jollow et al. , 1977). The growing interest in this field of research led to subsequent symposia at the University of Surrey, in England in 1980 (Snyder et al. , 1982), and the University of Maryland in the U. S. A. in 1985 (Kocsis et al. , 1986). The Fourth International Symposium on Biological Reactive Intermediates was hosted by the Center for Toxicology at the University of Arizona and convened in Tucson, Arizona, January 14-17, 1990. Over 300 people attended. There were 60 platform presentations by invited speakers, and 96 volunteer communications in the form of posters were offered. These meetings have grown from a small group of scientists working in closely related areas to a major international series of symposia which convene every five years to review, and place in context, the latest advances in our understanding of the formation, fate and consequences of biological reactive intermediates. The Organizing Committee: Allan H. Conney, Robert Snyder (Co-chairman), and Charlotte M. Witmer (Rutgers University, Piscataway, NJ), David J. Jollow Co­ chairman) (Medical University, South Carolina, Charleston, SC), 1. Glenn Sipes (Co­ chairman) (University of Arizona, Tucson, AZ), James J. Kocsis and George F. Front Matter....Pages i-xvii Cytochrome P-450 Oxidations and the Generation of Biologically Reactive Intermediates....Pages 1-11 Formation of Reactive Intermediates by Phase II Enzymes: Glutathione-Dependent Bioactivation Reactions....Pages 13-24 Role of the Well-Known Basic and Recently Discovered Acidic Glutathione S-Transferases in the Control of Genotoxic Metabolites....Pages 25-39 Bioactivation of Xenobiotics by Flavin-Containing Monooxygenases....Pages 41-50 Formation of Biological Reactive Intermediates by Peroxidases: Halide Mediated Acetaminophen Oxidation and Cytotoxicity....Pages 51-64 Peroxyl Free Radicals: Biological Reactive Intermediates Produced during Lipid Oxidation....Pages 65-70 Biological Significance of Active Oxygen Species: In Vitro Studies on Singlet Oxygen-Induced DNA Damage and on the Singlet Oxygen Quenching Ability of Carotenoids, Tocopherols and Thiols....Pages 71-77 Physiological and Toxicological Roles of Hydroperoxides....Pages 79-86 Overview: Theoretical Aspects of Isotope Effects on the Pattern of Metabolites Formed by Cytochrome P-450....Pages 87-94 S-Thiolation of Protein Sulfhydryls....Pages 95-103 Cytochrome P-450 as a Target of Biological Reactive Intermediates....Pages 105-109 Hapten Carrier Conjugates Associated with Halothane Hepatitis....Pages 111-120 Metabolism of Drugs by Activated Leukocytes: Implications for Drug-Induced Lupus and Other Drug Hypersensitivity Reactions....Pages 121-132 Formation of Reactive Metabolites and Appearance of Antiorganelle Antibodies in Man....Pages 133-137 Formation of a Protein-Acetaldehyde Adduct in Liver during Chronic Alcohol Exposure....Pages 139-149 Dose-Response Relationships in Chemical Carcinogenesis: From DNA Adducts to Tumor Incidence....Pages 151-156 The Single Cell Gel (SCG) Assay: An Electrophoretic Technique for the Detection of DNA Damage in Individual Cells....Pages 157-164 Monitoring Human Exposure to Environmental Carcinogens....Pages 165-181 Comparing the Frequency and Spectra of Mutations Induced When an SV40-Based Shuttle Vector Containing Covalently Bound Residues of Structurally-Related Carcinogens Replicates in Human Cells....Pages 183-191 Molecular Targets of Chemical Mutagens....Pages 193-209 Mutagenic Consequences of the Alteration of DNA by Chemicals and Radiation....Pages 211-223 Gene Specific Damage and Repair after Treatment of Cells with UV and Chemotherapeutical Agents....Pages 225-233 Proto-Oncogene Activation in Rodent and Human Tumors....Pages 235-243 Toxicity of 3-Methyleneoxindole, a Proposed Reactive Intermediate in the Metabolism of 3-Methylindole....Pages 245-248 The Role of Cytochrome P450IIE1 in Bioactivation of Acetaminophen in Diabetic and Acetone-Treated Mice....Pages 249-251 Arylamine-Induced Hemolytic Anemia: Electron Spin Resonance Spectrometry Studies....Pages 253-255 Selective Alterations in the Profiles of Newly Synthesized Proteins by Acetaminophen (APAP) and its Dimethylated Analogues: Relationship to Oxidative Stress....Pages 257-260 Benzene Metabolism by Two Purified, Reconstituted Rat Hepatic Mixed Function Oxidase Systems....Pages 261-265 Stereochemical Induction of Cytochrome P450IVA1 (P452) and Peroxisome Proliferation in Male Rat....Pages 267-270 Cyanide Liberation and Oxidative Stress by Organothiocyanates, Organonitriles and Nitroprusside in Isolated Hepatocytes....Pages 271-274 Mixed Function Oxidase Enzyme Responses to in Vivo and in Vitro Chromate Treatment....Pages 275-280 Fatty Acid β-Oxidation-Dependent Bioactivation of 5,6-Dichloro-4-Thia-5-Hexenoate and Analogs in Isolated Rat Hepatocytes....Pages 281-284 Role of the Acetone Inducible P-450IIE1 in the Deethylation of Diethylnitrosamine in Hamster....Pages 285-287 Stereochemistry of the Microsomal Glutathione S -Transferase-Catalyzed Addition of Glutathione to Chlorotrifluoroethene in Isolated Rat Hepatocytes....Pages 289-293 The Pathophysiological Significance of Reactive Oxygen Formation in Rat Liver....Pages 295-298 Oxidative Stress during Hypoxia in Isolated-Perfused Rat Heart....Pages 299-304 Alteration of Growth Rate and Fibronectin by Imbalances in Superoxide Dismutase and Glutathione Peroxidase Activity....Pages 305-309 The Antidotal Activity of the Thiol Drug Diethyldithiocarbamate Against N-Acetyl-p-Benzoquinone Imine in Isolated Hepatocytes....Pages 311-314 Two Classes of Azo Dye Reductase Activity Associated with Rat Liver Microsomal Cytochrome P-450....Pages 315-321 Expression of a cDNA Encoding Rat Liver DT-Diaphorase in Escherichia Coli ....Pages 323-327 Suicidal Inactivation of Cytochrome P-450 by Halothane and Carbon Tetrachloride....Pages 329-332 Structure-Activity Relationships of Acrylate Esters: Reactivity Towards Glutathione and Hydrolysis by Carboxylesterase in Vitro ....Pages 333-335 Glutathione Conjugates of Hydralazine Formed in Theperoxidase/Hydrogen Peroxide/Glutathione System....Pages 337-342 Contribution of 3,4-Dichlorophenylhydroxylamine in Propanil-Induced Hemolytic Anemia....Pages 343-345 A Reduction in Mixed Function Oxidases and in Tumor Promoting Effects of Ethanol in a NDEA-Initiated Hepatocarcinogenesis Model....Pages 347-352 Selective Inducers of the Coh-Locus Enhance the Metabolisms of Coumarin- and of Quinoline-Derivatives but Not That of Naphthalenes....Pages 353-357 Primaquine-Induced Oxidative Stress in Isolated Hepatocytes as a Result of Reductive Activation....Pages 359-363 Nitroprusside: A Potpourri of Biologically Reactive Intermediates....Pages 365-369 Denitrosation of N -Nitrosodimethylamine in the Rat in Vivo ....Pages 371-375 Effect of Phenol and Catechol on the Kinetics of Human Myeloperoxidase-Dependent Hydroquinone Metabolism....Pages 377-381 Activation of 1-Hydroxymethylpyrene to an Electrophilic and Mutagenic Metabolite by Rat Hepatic Sulfotransferase Activity....Pages 383-391 Bioactivation of 2,6-Di-Tert-Butyl-4-Methyl Phenol (BHT) and Hydroxylated Analogues to Toxic Quinoid Metabolites....Pages 393-398 Further Evidence for the Role of Myeloperoxidase in the Activation of Benzo[A]Pyrene-7,8-Dihydrodiol by Polymorpho-Nuclear Leukocytesm....Pages 399-401 Quinones and their Glutathione Conjugates as Irreversible Inhibitors of Glutathione S-Transferases....Pages 403-406 Cytochrome P450 IA2 Activity in Man Measured by Caffeine Metabolism: Effect of Smoking, Broccoli and Exercise....Pages 407-411 Tissue Difference in Expression of Cytochrome P-450 between Liver and Lung of Syrian Golden Hamsters Treated with 3- Methylcholanthrene....Pages 413-417 Role of Calcium in Toxic and Programmed Cell Death....Pages 419-425 Molecular Mechanisms of y -Diketone Neuropathy....Pages 427-431 Microtubule Assembly is Altered Following Covalent Modification by the n -Hexane Metabolite 2,5-Hexanedione....Pages 433-442 The Role of Hepatic Metabolites of Benzene in Bone Marrow Peroxidase-Mediated Myelo- and Genotoxicity....Pages 443-455 Glutathione Conjugation as a Mechanism of Targeting Latent Quinones to the Kidney....Pages 457-464 Hepatic Bioactivation of 4-Vinylcyclohexene to Ovotoxic Epoxides....Pages 465-470 Testicular Metabolism and Toxicity of Halogenated Propanes....Pages 471-476 Lung Vascular Injury from Monocrotaline Pyrrole, a Putative Hepatic Metabolite....Pages 477-487 Reactive Oxygen Species in the Progression of CCl 4 -Induced Liver Injury....Pages 489-497 Parenchymal and Nonparenchymal Cell Interactions in Hepatotoxicity....Pages 499-505 Signal Paths and Regulation of Superoxide, Eicosanoid and Cytokine Formation in Macrophages of Rat Liver....Pages 507-520 Reactive Metabolites from N-Nitrosamines....Pages 521-524 Bisfuranoid Mycotoxins: Their Genotoxicity and Carcinogenicity....Pages 525-532 Covalent Bonding of Bay-Region Diol Epoxides to Nucleic Acids....Pages 533-553 Electrophilic Sulfuric Acid Ester Metabolites of Hydroxy-Methyl Aromatic Hydrocarbons as Precursors of Hepatic Benzylic DNA Adducts in Vivo....Pages 555-567 Heterocyclic Amines: New Mutagens and Carcinogenes in Cooked Foods....Pages 569-578 Acetaminophen and Protein Thiol Modification....Pages 579-588 Formation and Reactivity of a Quinone Methide in Biological Systems....Pages 589-596 Mechanisms for Pyrrolizidine Alkaloid Activation and Detoxification....Pages 597-603 Sulfur Conjugates as Putative Pneumotoxic Metabolites of the Pyrrolizidine Alkaloid, Monocrotaline....Pages 605-612 The Metabolism of Benzene to Muconic Acid, a Potential Biological Marker of Benzene Exposure....Pages 613-618 Lessons on the Second Cancers Resulting from Cancer Chemotherapy....Pages 619-625 Genetic Polymorphism of Drug Metabolism in Humans....Pages 627-640 Human Health Risk Assessment and Biological Reactive Intermediates: Hemoglobin Binding....Pages 641-647 Quantitating the Production of Biological Reactive Intermediates in Target Tissues: Example, Dichloromethane....Pages 649-655 Trapping of Reactive Intermediates by Incorporation of 14 C-Sodium Cyanide during Microsomal Oxidation....Pages 657-664 Multiple Bioactivation of Chloroform: A Comparison Between Man and Experimental Animals....Pages 665-667 CCl 4 -Induced Cytochrome P-450 Loss and Lipid Peroxidation in Rat Liver Slices....Pages 669-674 Alteration of Benzo(A)Pyrene-DNA Adduct Formation by Rats Exposed to Simple Mixtures....Pages 675-679 Comparison of the Toxicity of Naphthalene and Naphthalene-1,2-Dihydrodiol (DIOL)....Pages 681-684 Selective Binding of Acetaminophen (APAP) to Liver Proteins in Mice and Men....Pages 685-688 Post-Treatment Protection with Piperonyl Butoxide Against Acetaminophen Hepatotoxicity is Associated with Changes in Selective but Not Total Covalent Binding....Pages 689-692 Covalent Binding of a Halothane Metabolite and Neoantigen Production in Guinea Pig Liver Slices....Pages 693-697 Extensive Alteration of Genomic DNA and Rise in Nuclear Ca 2+ in Vivo Early after Hepatotoxic Acetaminophen Overdose in Mice....Pages 699-705 The Possible Role of Glutathione on the Hepatotoxic Effect of Papaverine Hydrochloride in Vitro ....Pages 707-709 In Vivo and in Vitro Evidence for in Situ Activation and Selective Covalent Binding of Acetaminophen (APAP) in Mouse Kidney....Pages 711-716 Metabolism of Dichlorobenzenes in Organ Cultured Liver Slices....Pages 717-723 Inhibition of Protein Synthesis and Secretion by Volatile Anesthetics in Guinea Pig Liver Slices....Pages 725-730 Dichlorobenzene Hepatotoxicity Strain Differences and Structure Activity Relationships....Pages 731-734 The Use of 19 F NMR in the Study of Protein Alkylation by Fluorinated Reactive Intermediates....Pages 735-738 S-Ethylthiotrifluoroacetate Enhancement of the Immune Response to Halothane in the Guinea Pig....Pages 739-744 Bone Marrow DNA Adducts and Bone Marrow Cellularity Following Treatment with Benzene Metabolites in Vivo ....Pages 745-748 The Role of γ-Glutamyl Transpeptidase in Hydroquinone-Glutathione Conjugate Mediated Nephrotoxicity....Pages 749-751 Cytochrome P450IIE1 Metabolism of Pyridines: Evidence for Production of a Reactive Intermediate which Exhibits Redox-Cycling Activity and Causes DNA Damage....Pages 753-758 Morphological Cell Transformation and DNA Adduction by Benz(J)Aceanthrylene and its Presumptive Reactive Metabolites in C3H10T1/2CL8 Cells....Pages 759-762 Covalent Binding of Oxidative Biotransformation Reactive Intermediates to Protein Influences Halothane-Associated Hepatotoxicity in Guinea Pigs....Pages 763-766 The Nephrotoxicity of 2,5-Dichloro-3-(Glutathion-S-YL)-1,4-Benzo-Quinone, and 2,5,6-Trichloro-3-(Glutathion-S-YL)-1,4-Benzoquinone is Potentiated by Ascorbic Acid and AT-125....Pages 767-769 Generation of Free Radicals Results in Increased Rates of Protein Degradation in Human Erythrocytes....Pages 771-776 Free Radicals Generated in Ethanol Metabolism May Be Responsible for Tumor Promoting Effects of Ethanol....Pages 777-783 Composition of Hepatic Lipids after Ethanol, Cod Liver Oil and Vitamin E Feeding in Rats....Pages 785-788 Dietary Polyunsaturated Fatty Acid Promote Peroxidation and its Possible Role in the Promotion of Cancer....Pages 789-791 Chiral Epoxides, their Enantioselective Reactivity Towards Nucleic Acids, and a First Outline of a Quantum Chemical Structure-Reactivity Calculation....Pages 793-799 Comparison of 8-Hydroxydeoxyguanosine and 5-Hydroxymethyluracil as Products of Oxidative DNA Damage....Pages 801-803 Modulation of Aortic Smooth Muscle Cell Prolifertion by Dinitrotoluene....Pages 805-808 Reactive Potential of Diethylstilbestrol Reactive Metabolites Towards Cellular Nuclear Proteins: Implications for Estrogen*Induced Carcinogenesis....Pages 809-812 Biochemical and Morphologic Response of Nasal Epithelia to Hyperoxia....Pages 813-816 Membrane Stabilization as a Fundamental Event in the Mechanism of Chemoprotection Against Chemical Intoxication....Pages 817-819 Biochemical Effects and Toxicity of Mitoxantrone in Cultured Heart Cells....Pages 821-825 Evidence for the Induction of an Oxidative Stress in Rat Hepatic Mitochondria by 2,3,7,8-Tetrachlorodibenzo-P-Dioxin (TCDD)....Pages 827-831 Antioxidation Potential of Indole Compounds — Structure Activity Studies....Pages 833-836 Measurement of Styrene-Oxide Cysteine Adducts in Hemoglobin by Selective Catalytic Reduction....Pages 837-841 Studies on Biochemical Determinants of Quinone-Induced Toxicity in Primary Murine Bone Marrow Stromal Cells....Pages 843-846 Selective Alteration of Cytokeratin Intermediate Filament by Cyclosporine A is a Lethal Toxicity in PTK2 Cell Cultures....Pages 847-851 Rat Hepatic DNA Damage Induced by 1,2,3-Trichloropropane....Pages 853-855 Oxidation of Reduced Porphyrins by the Mitochondrial Electron Transport Chain: Stimulation by Iron and Potential Role of Reactive Oxygen Species....Pages 857-862 Future Research Needs for the Application of Mechanistic Data to Risk Assessment....Pages 863-868 Back Matter....Pages 869-894 The finding that chemicals can be metabolically activated to yield reactive chemical species capable of covalently binding to cellular macromolecules and the concept that these reactions could initiate toxicological and carcinogenic events stimulated a meeting by a small group of toxicologists at the University of Turku, in Finland, in 1975 (Jollow et al., 1977). The growing interest in this field of research led to subsequent symposia at the University of Surrey, in England in 1980 (Snyder et al., 1982), and the University of Maryland in the U.S.A. in 1985 (Kocsis et al., 1986). The Fourth International Symposium on Biological Reactive Intermediates was hosted by the Center for Toxicology at the University of Arizona and convened in Tucson, Arizona, January 14-17, 1990. Over 300 people attended. There were 60 platform presentations by invited speakers, and 96 volunteer communications in the form of posters were offered. These meetings have grown from a small group of scientists working in closely related areas to a major international series of symposia which convene every five years to review, and place in context, the latest advances in our understanding of the formation, fate and consequences of biological reactive intermediates. The Organizing Committee: Allan H. Conney, Robert Snyder (Co-chairman), and Charlotte M. Witmer (Rutgers University, Piscataway, NJ), David J. Jollow CoƯ chairman) (Medical University, South Carolina, Charleston, SC), 1. Glenn Sipes (CoƯ chairman) (University of Arizona, Tucson, AZ), James J. Kocsis and George F