Biological Reactive Intermediates III: Mechanisms of Action in Animal Models and Human Disease (Advances in Experimental Medicine and Biology, 197)

This volume contains the proceedings of the third in a series of conferences entitled, The International Symposium on Biological Reactive Intermediates. The first was held at the University of Turku in Finland, in 1975, the second at the University of Surrey in the United Kingdom, in 1980 and the most recent at the University of Maryland in the United States, in 1985. The significance of these conferences has been emphasized by the rapid growth of mechanistic toxicology over the last decade. These conferences were initially stimulated by the attempt to uncover the significance behind the observations that the toxicity of carcinogenic responses produced by many chemicals was associated with the observation that their metabolism led to the formation of chemcially reactive electrophiles which covalently bound to nucleophilic sites in cells such as proteins, nucleic acid or fats. Recently, newer concepts have arisen which have necessitated the expansion of subjects covered by the conference. For example, the application of newer knowledge of the role of active oxygen species in reactive metabolite formation, the concept of suicide substrates, examination of the function of glutathione in cells, application of immunological techniques and molecular biological probes to the solution of toxicological problems all had an impact on the study of the biological reactive intermediates. Front Matter....Pages i-xv Years with Elizabeth and James Miller: in Appreciation....Pages 1-9 Reactivity and Tumorigenicity of Bay-Region Diol Epoxides Derived from Polycyclic Aromatic Hydrocarbons....Pages 11-30 Chemistry of Covalent Binding: Studies with Bromobenzene and Thiobenzamide....Pages 31-40 Role of Thiols in Protection Against Biological Reactive Intermediates....Pages 41-51 Role of Parenchymal Versus Non-Parenchymal Cells on the Control of Biologically Reactive Intermediates....Pages 53-61 Significance of Covalent Binding of Chemically Reactive Metabolites of Foreign Compounds to Proteins and Lipids....Pages 63-82 Structure and Function of Cytochrome P-450....Pages 83-94 Antibodies as Probes of Cytochrome P450 Isozymes....Pages 95-106 Age and Sex Differences in Constitutive Forms of Cytochrome P-450 of Rat Liver Microsomes....Pages 107-117 Identification of Intratissue Sites for Xenobiotic Activation and Detoxication....Pages 119-144 Monoclonal Antibody-Directed Analysis of Cytochrome P-450....Pages 145-154 Drug Interactions with Macrolide Antibiotics: Specificity of Pseudo-Suicide Inhibition and Induction of Cytochrome P-450....Pages 155-162 Isomeric Composition of N -Alkylated Protoporphyrins Produced by Substituted Dihydropyridines in Vivo and in Vitro ....Pages 163-170 UDP-Glucuronyltransferases and Their Toxicological Significance....Pages 171-184 Expression and Sequence Analysis of Rat Liver Glutathione S-Transferase Genes....Pages 185-193 Rat Cytosolic Epoxide Hydrolase....Pages 195-201 Multiplicity of Cytochrome P-450 in Morris Hepatoma....Pages 203-212 The Metabolism of Benzene and Phenol by a Reconstituted Purified Phenobarbital-Induced Rat Liver Mixed Function Oxidase System....Pages 213-222 Comparison of the Metabolism of Benzene and Its Metabolite Phenol in Rat Liver Microsomes....Pages 223-235 Further Evidence for a Role of Isozymes of P450 in the Metabolism and Toxicity of Carbon Disulfide (CS 2 )....Pages 237-242 Effect of a Suicide Substrate on the Metabolism of Steroids and Xenobiotics and on Cytochrome P-450 Apoproteins....Pages 243-251 Activation of Cytochrome P-450 Heme in Vivo ....Pages 253-261 The FAD-Containing Monooxygenase of Lung and Liver Tissue from Rabbit, Mouse and Pig: Species and Tissue Differences....Pages 263-272 Oxygen Radical Formation During Redox Cycling of Bleomycin-Fe(III) Catalyzed by NADPH-Cytochrome P-450 Reductase of Liver Microsomes and Nuclei....Pages 273-280 Superoxide Dismutase Modification and Genotoxicity of Transition-Metal Ion Chelators....Pages 281-290 Toxicologic Implications of the Iron-Dependent Activation of Bleomycin A 2 by Mouse Lung Microsomes....Pages 291-300 The Peroxidative Activation of Butylated Hydroxytoluene to BHT-Quinone Methide and Stilbenequinone....Pages 301-309 Activation of Xenobiotics by Human Polymorphonuclear Leukocytes via Reactive Oxygen-Dependent Reactions....Pages 311-321 Metabolism of Diehtylstilbestrol by Horseradish Peroxidase and Prostaglandin Synthase — Evidence for a Free Radical Intermediate....Pages 323-328 Thiyl Radicals--Their Generation and Further Reactions....Pages 329-335 Mechanism of the Cytochrome P-450 Catalyzed Isomerization of Hydroperoxides....Pages 337-346 Indole-3-carbinol Inhibits Lipid Peroxidation in Cell-Free Systems....Pages 347-356 Glutathione Peroxidase and Reactive Oxygen Species in TCDD-Induced Lipid Peroxidation....Pages 357-365 Activation of Nitrosamines to Mutagens by Rat and Rabbit Nasal, Lung and Liver S-9 Homogenates....Pages 367-372 Structure of the Adduct of Glutathione and Activated 3-Mathylindole....Pages 373-380 Studies on the Mechanism of S -Cysteine Conjugate Metabolism and Toxicity in Rat Liver, Kidney, and a Cell Culture Model....Pages 381-390 Formation and Identification of Naphthoquinone Glutathione Conjugates Following Microsomal Metabolism of 1-Naphthol....Pages 391-397 The Formation of N-Glucuronides Catalyzed by Purified Hepatic 17β-Hydroxysteroid and 3α-Hydroxysteroid UDP-Glucuronyltransferases....Pages 399-405 Improved Method for Determination of Cellular Thiols, Disulfides and Protein Mixed Disulfides Using HPLC with Electrochemical Detection....Pages 407-413 Arylsulfotransferase IV Catalyzed Sulfation of 1-Naphthalenemethanol....Pages 415-422 Activated Phase II Metabolites: Comparison of Alkylation by 1-0-Acyl Glucuronides and Acyl Sulfates....Pages 423-429 Reactions of Oxaprozin-1-0-Acyl Glucuronide in Solutions of Human Plasma and Albumin....Pages 431-441 Nephrotoxic Amino Acid and Glutathione S -Conjugates: Formation and Renal Activation....Pages 443-455 The Role of Glutathione in the Toxicity of Xenobiotic Compounds: Metabolic Activation of 1,2-Dibromoethane by Glutathione....Pages 457-467 A Comparison of the Alkylating Capabilities of the Cysteinyl and Glutathionyl Conjugates of 1,2-Dichloroethane....Pages 469-475 Covalent Reactions in the Toxicity of SO 2 and Sulfite....Pages 477-492 One- and Two-Electron Oxidation of Reduced Glutathione by Peroxidases....Pages 493-503 Reactive Oxygen Species Formed in Vitro and in Cells: Role of Thiols(GSH). Model Studies with Xanthine Oxidase and Horseradish Peroxidase....Pages 505-512 Active Oxygen and Toxicity....Pages 513-526 Studies on the Mechanism of Activation and the Mutagenicity of Ronidazole, a 5-Nitroimidazole....Pages 527-535 Carcinogen-DNA Adduct Formation as a Predictor of Metabolic Activation Pathways and Reactive Intermediates in Benzidine Carcinogenesis....Pages 537-549 Purification, Properties and Function of N-Hydroxyarylamine O- Acetyltransferase....Pages 551-561 Metabolism and Carcinogenicity of Nitrotoluenes....Pages 563-571 Hydroxylamines and Hemolytic Anemia....Pages 573-582 Electrophilic Sulfuric Acid Ester Metabolites as Ultimate Carcinogens....Pages 583-595 Biological Reactive Intermediates of Mycotoxins....Pages 597-610 Biological Reactive Intermediates of Pyrrolizidine Alkaloids....Pages 611-620 Mutagens and Carcinogens Formed During Cooking....Pages 621-629 Quinone Imines as Biological Reactive Intermediates....Pages 631-644 The Role of Reactive Intermediates in Sulfhydryl-Dependent Immunotoxicity: Interference with Microtubule Assembly and Microtubule-dependent Cell Function....Pages 645-655 Investigation of the Immunological Basis of Halothane-Induced Hepatotoxicity....Pages 657-673 Inhibition of RNA Synthesis in Mouse Macrophages and Lymphocytes by Benzene and Its Metabolites....Pages 675-690 p-Nitrosophenetole: A Reactive Intermediate of Phenacetin that Binds to Protein....Pages 691-696 Mechanism of Fasting-Induced Suppression of Acetaminophen Glucuronidation in the Rat....Pages 697-706 Effect of Diethyl Ether on the Bioactivation, Detoxification, and Hepatotoxicity of Acetaminophen in Vitro and in Vivo....Pages 707-715 Piperonyl Butoxide Reduces Salicylate-Induced Nephrotoxicity and Covalent Binding in Male Rats....Pages 717-726 Cross-Linking of Protein Molecules by the Reactive Metabolite of Acetaminophen, N -Acetyl- p -Benzoquinone Imine, and Related Quinoid Compounds....Pages 727-737 Acetaminophen as a Cosubstrate and Inhibitor of Prostaglandin H Synthase....Pages 739-747 The Fate of 4-Cyanoacetanilide in Rats and Mice: The Mechanism of Formation of a Novel Electrophilic Metabolite....Pages 749-753 Mechanistic Studies of Acetamide Hepatocarcinogenicity....Pages 755-762 Reactions of Glutathione with Oxidative Intermediates of Acetaminophen....Pages 763-772 Flavin-Containing Monooxygenase Activity in Human Liver Microsomes....Pages 773-779 S9-Dependent Activation of 1-Nitropyrene and 3-Nitrofluoranthene in Bacterial Mutagenicity Assays....Pages 781-788 Formation of a Ring-Opened Product from Benzene in a Hydroxyl Radical Generating System....Pages 789-795 H-2 Modulation of Aryl Hydrocarbon Hydroxylase Induction and the Mutagenicity of Benzo(a)Pyrene after 3-Methylcholanthrene Treatment....Pages 797-807 Stereoselectivity of Rat Liver Cytochrome P-450 Isozymes: Direct Determination of Enantiomeric Composition of K-Region Epoxides Formed in the Metabolism of Benz[A]Anthracene and 7,12-Dimethylbenz[A]Anthracene....Pages 809-818 Induction of Unscheduled DNA Synthesis in Human Mononuclear Leukocytes by Oxidative Stress....Pages 819-823 Deoxyguanosine Adducts Formed from Benzoquinone and Hydroquinone....Pages 825-832 3-Hydroxy- Trans -7,8-Dihydro-7,8-Dihydroxy-Benzo(a)Pyrene, a Metabolite of 3-Hydroxybenzo(a)Pyrene....Pages 833-842 Time Course of the Effect of 4-Hydroperoxycyclophosphamide on Limb Differentiation in Vitro....Pages 843-852 Hepatic Pathological Changes Due to Hydroxyalkenals....Pages 853-860 Clofibrate Selectively Induces Azoreduction of Dimethylaminoazobenzene (DAB) by Rat Liver Microsomes....Pages 861-870 Intracellular Dissipative Structures (IDS) as Ultimate Targets of Chemical Cytotoxicity....Pages 871-889 Helenalin: Mechanism of Toxic Action....Pages 891-896 Evidence for Stereoselective Production of Phenytoin (5,5-Diphenylhydantoin) Arene Oxides in Man....Pages 897-902 Tissue Distribution and Covalent Binding of [ 14 C]1,1-Dichloroethylene in Mice: In vivo and in vitro Studies....Pages 903-910 Inhibition of Respiration in Rabbit Proximal Tubules by Bromophenols and 2-Bromohydroquinone....Pages 911-917 In Vitro Covalent Binding of 14 C-Mibolerone to Rat Liver Microsomes....Pages 919-924 Chemistry of Metabolites of Thioureas....Pages 925-929 Conversion of Phenytoin to Reactive Metabolites in Rat Liver Microsomes....Pages 931-939 Comparison of N-Methylformamide-Induced Hepatotoxicity and Metabolism in Rats and Mice....Pages 941-950 Epoxidation of 1,3-Butadiene in Liver and Lung Tissue of Mouse, Rat, Monkey and Man....Pages 951-957 Enzyme Catalysed Cleavage of the N-N Bond of N-Nitrosamines....Pages 959-970 Use of the Chemiluminigenic Probes Luminol and Lucigenin for the Detection of Active Oxygen Species in Hepatic Microsomes and in Intact Hepatocytes....Pages 971-980 Altered Expression of Oncogenes in Mouse Epidermis Following Exposure to Benzo(A)Pyrene Diol Epoxides....Pages 981-992 Acetaminophen Toxicity in Isolated Hepatocytes....Pages 993-1003 Mechanism of Organ Specificity in Nitrosamine Carcinogenesis....Pages 1005-1011 Biological Reactive Metabolites in Human Toxicity....Pages 1013-1016 Metabolic Host Factors as Modifiers of Reactive Intermediates Possibly Involved in Human Cancer....Pages 1017-1027 Closing Remarks....Pages 1029-1037 Back Matter....Pages 1039-1059