Biological Reactive Intermediates: Formation, Toxicity, and Inactivation PDF
Preview Biological Reactive Intermediates: Formation, Toxicity, and Inactivation
Biological Reactive Intermediates Formation, Toxicity, and Inactivation Biological Reactive Intermediates Formation, Toxicity, and Inactivation Edited by David J. Jollow Medical University of South Carolina, Charleston James J. Kocsis Thomas Jefferson University, Philadelphia Robert Snyder Thomas Jefferson University, Philadelphia and Harri Vainio Institute of Occupational Health, Helsinki Associate Editors Jussi Saukkonen and Charlotte Witmer Thomas Jefferson University, Philadelphia and Thomas Walle Medical University of South Carolina, Charleston PLENUM PRESS· NEW YORK AND LONDON Library of Congress Cataloging in Publication Data Main entry under title: Biological reactive intermediates. Includes bibliographical references and index. 1. Toxicology-Congresses. 2. Biotransformation (Metabolism)-Congresses. 3. Carcinogenesis-Congresses. I. Jollow, David J. II. Turku, Finland Yliopisto. [DNLM: 1. Biotransformation-Congresses. QV38 1603b 19751 RA1191.B56 615'.7'04 76-55724 ISBN 0-306-30970-X Proceedings of an International Conference on Active Intermediates: Formation, Toxicity, and Inactivation, held at the University of Turku, Turku, Finland, July 26-27,1975 © 1977 Plenum Press, New York A Division of Plenum Publishing Corporation 227 West 17th Street, New York, N.Y. 10011 All rights reserved No part of this book may be reproduced, stored in a retrieval system, or transmitted, in any form or by any means, electronic, mechanical, photocopying, microfilming, recording, or otherwise, without written permission from the Publisher Preface The concept that detoxication is the inevitable result of biotransformation of xenobiotic compounds by mammalian systems has undergone modification since it was first described. Indeed, despite the fact that R. T. Williams popularized the notion, he was among the first to caution that it was not possible to predict the biological activities of the resulting metabolites. It has become increasingly apparent in recent years that not only do many metabolites of drugs and other chemicals display biological activity but also in many instances these metabolites play an important role in initiating several forms of cancer and are the cause of a variety of types of toxicity. Thus it seems appropriate to collect in one volume a series of reports outlining advances in the study of the formation of chemically active intermediary metabolic products of chemicals, mechanisms of toxicity or carcinogenesis, and pathways for true detoxication of these chemicals. The work of R. T. Williams, beginning in the late 1920s and early 1930s, marked the first concerted effort to understand the biotransformation of foreign chemicals in animals. He investigated the metabolic pathway of numerous compounds in a wide variety of animal species while training large numbers of our colleagues who have been responsible for further advances in biochemistry, pharmacology, and toxicology. Another pioneer in the study of drug metabo lism, B. B. Brodie, was unable to take part in this presentation, but his significant contributions included not only laying the groundwork for the study of human drug metabolism and pharmacokinetics but also teaching many of the participants in this work. The fundamental contributions of H. Remmer to our understanding of enzyme induction and cytochrome P450 as well as his vigorous attempts to promote international scientific interchanges are also worthy of our acclaim. Certainly no one has contributed more to our understanding of meta bolic activation of xenobiotics and their covalent bonding to critical cellular elements than J. A. and E. C. Miller. These workers were among the first to demonstrate the metabolism of foreign compounds in vitro using liver mi crosomal preparations, they were the first to demonstrate enzyme induction by polycyclic aromatic hydrocarbons, and they have shown that many carcinogenic and mutagenic chemicals undergo metabolism to reactive electrophilic inter mediates that exert toxic effects by binding to critical sites on DNA, proteins, and other macromolecules. We are fortunate in having all of these scientists v vi Preface represented in this volume either directly or through their selected representa tives and it is to them that we dedicate this book. The papers published in this volume represent the proceedings of an inter national conference entitled Active Intermediates: Formation, Toxicity, and Inactivation which convened at the University of Turku, Turku, Finland, luly 26-27,1975. The conference was organized by a committee composed of Drs. 1. F. Borzelleca, 1. R. Gillette, O. Hanninen, D. 1. lollow (Cochairman), 1. 1. Kocsis, H. Remmer, R. Snyder (Cochairman), and H. Vainio (Cochairman). The chairmen wish to express their deep appreciation to Dr. Gillette for his produc tive efforts during the organization of the program. The conference would not have been possible without the generous support, encouragement, and participation of a number of individuals and organizations. Among these were the National Institute of Environmental Health Sciences of the National Institutes of Health, Professor K. Hartiala and the University of Turku, the Turku University Foundation, the Ministry of Education of Finland, Thomas lefferson University, Philadelphia, Pennsylvania, the Rohm and Haas Company, the Hoffman-LaRoche Company, the Haskell Laboratories of E. I. DuPont de Nemours and Company, and Laake Oy, Turku, Finland. The editors decided not to present a verbatim reproduction of the discussion that accompanied each group of papers presented at the conference. Instead, Drs. 1. Saukkonen and C. M. Witmer of Thomas 1e fferson University and Dr. T. Walle of the Medical University of South Carolina prepared summaries of the discussions with the intent of presenting only their salient features in a concise manner. We also wish to express our gratitude to Drs. R. T. Williams, K. 1. Netter, 1. A. Miller, S. Orrenius, R. Sato, and H. Gelboin for their efforts as session chairmen. We wish to acknowledge the hospitality, the facilities, and the stimulating scientific atmosphere that we enjoyed in Turku. International cooperation and exchange of ideas should never be considered extraordinary. Communication is the lifeblood of science. That our fundamental purpose can be achieved while enjoying cordial relationships with our colleagues around the world is a fringe benefit of untold value. D.l.l. 1.1. K. R.S. H.V. Contents I. Reactive Intermediates in Toxicology and Carcinogenesis: Role of Covalent Binding 1. Introduction to the Concept of Reactive Intermediates ............. 3 R. T. Williams 2. The Concept of Reactive Electrophilic Metabolites in Chemical Carcinogenesis: Recent Results with Aromatic Amines, Safrole, and Aflatoxin BI ............................................. 6 James A. Miller and Elizabeth C. Miller 3. Kinetics of Reactive Metabolites and Covalent Binding in Vivo and in Vitro ................................................... 25 James R. Gillette 4. Biochemical Aspects of Toxic Metabolites: Formation, Detoxication, and Covalent Binding ...................................... 42 David J. Jollow and Carole Smith 5. Discussion ............................................... 60 II. Formation of Reactive Intennediates 6. Mechanism of Microsomal Monooxygenases and Drug Toxicity ....... 65 Volker Ullrich 7. Discussion ............................................... 81 8. Aryl Hydrocarbon Hydroxylase: Induction ...................... 83 John B. Schenkman, Kathy M Robie, and Ingela Jansson 9. Discussion ............................................... 96 vii viii Contents 10. Benzo [a] pyrene Metabolism: Enzymatic and Liquid Chromatographic Analysis and Application to Human Liver, Lymphocytes, and Monocytes ............................................... 98 Harry V. Gelboin, James Selkirk, Takao Okuda, Nobuo Nemoto, Shen K. Yang, Friedrich 1. Wiebel, James P. Whitlock, Jr., Herbert J. Rapp, and Robert C Bast, Jr. 11. Discussion ............................................... 124 12. Genetic Differences in Benzo [a] pyrene Carcinogenic Index in Vivo and in Mouse Cytochrome PI 450·Mediated Benzo [a] pyrene Metabolite Binding to DNA in Vitro .................................... 125 Daniel W. Nebert, Alan R. Boobis, Haruhiko Yagi, Donald M Jerina, and Richard E. Kouri 13. Discussion .............................................. 146 14. Formation of Toxic Intermediates in Fetal Tissues ................ 148 Olavi Pelkonen 15. Discussion ............................................... 160 16. The Possible Role of Trout Liver Aryl Hydrocarbon Hydroxylase in Activating Aromatic Polycyclic Carcinogens* .................... 162 Jorma T. Ahokas, Olavi Pelkonen, and Niilo T. Kiirki 17. Metabolic Activation of Methyldopa by Cytochrome P450-Generated Superoxide Anion* ........................................ 167 E. Dybing, J. R. Mitchell, S. D. Nelson, and J. R. Gillette 18. Formation of Tertiary Amine N-Oxide and Its Reduction by Rat Liver Microsomes* ............................................. 173 Ryuichi Kato, Hideyo Noguchi, Masahiko Sugiura, and Kazuhide Iwasaki III. Inactivation of Reactive Intermediates 19. Epoxide Hydratase: Purification to Apparent Homogeneity as a Specific Probe for the Relative Importance of Epoxides among Other Reactive Metabolites ....................................... 181 F. Oesch, P. Bentley, and H. R. Glatt 20. Glutathione S-Transferases .................................. 207 Donald M. Jerina and John R. Bend *Poster sessions. Contents ix 21. Discussion ............................................... 237 22. UDPGlucuronosyltransferase: Substrate Specificity and Reactivation after Partial Separation from Other Membrane Components ......... 239 Osmo Hiinninen, Matti Lang, Ulla Koivusaari, and Tuula Ollikainen 23. Discussion ............................................... 250 24. Inactivation of Reactive Intermediates in Human liver ............. 251 Ham Vainio, Jukka Marniemi, Max Parkki, and Reijo Luoma 25. Discussion ............................................... 263 26. Nucleotide Pyrophosphatase as a Competitor of Drug Hydroxylation and Conjugation in Rat Liver Microsomes . . ..................... 264 Eino Puhakainen IV. Specific Reactive Intermediates 27. Metabolic Activation of Hydrazines to Highly Reactive Hepatotoxic Intermediates ... _ -_. .............. _. ..................... 271 Jerry R. Mitchell, Sidney D. Nelson, Wayne R. Snodgrass, and John A. Timbrel! 28. Discussion .............................. _. ............... 278 29. Activation of Nitrite ....................................... 279 William Lijinsky 30. Discussion ............................................... 284 31. Benzene Metabolism and Toxicity ............................. 286 R. Snyder, L. S. Andrews, E. W. Lee, C M. Witmer, M. Reilly, and J. J. Kocsis 32. Benzene and p-Xylene: A Comparison of Inhalation Toxicities and in Vitro Hydroxylations ...................................... 302 C Harper, R. T. Drew, and J. R. Fouts 33. Discussion ............................................... 312 34. Hepatotoxicity of Carbon Disulfide and of Other Sulfur-Containing Chemicals: Possible Significance of Their Metabolism by Oxidative Desulfuration ............................................ 314 Francesco De Matteis x Contents 35. Studies of the Formation of Reactive Intermediates of Parathion ..... 320 Robert A. Neal, Tetsuya Kamataki, Marie Lin, Kay A. Ptashne, Ramesh R. Dalvi, and Raymond E. Poore 36. Discussion ............................................... 333 37. Metabolism and Biological Activity of Benzo[a]pyrene and Its Metabolic Products ........................................ 335 A. H. Conney, A. W. Wood, W. Levin, A. Y. H. Lu, R. L. Chang, P. G. Wislocki, R. L. Goode, G. M Holder, P. M. Dansette, H. Yagi, and D. M Jerina 38. Discussion ............................................... 357 39. Polycyclic Hydrocarbon Epoxides as Active Metabolic Intermediates .. 358 Peter Sims 40. Stereoselective Synthesis and Reactions of a Diol-Epoxide Derived from Benzo[a] pyrene .......................................... 371 Donald M. Jerina, Haruhiko Yagi, and Oscar Hernandez 41. Discussion ............................................... 379 42. Additional Routes in the Metabolism of Phenacetin * .............. 380 Tilman Fischbach, Werner Lenk, and Dieter Sackerer 43. Biliary Metabolites of Paracetamol in Relation to Dose Level and Various Pretreatments* ..................................... 387 A. Malnoe, M Strolin Benedetti, R. L. Smith, and A. Frigerio 44. Studies on Pharmacokinetics of N-Demethyldiazepam, the Active Main Metabolite of Diazepam* ................................... 394 Lauri Kangas, Jussi Kanto, Raija Sellman, and Aimo Pekkarinen V. Reactive Intermediates in Lipid Peroxidation 45. Regulation and Effects of Lipid Peroxidation in Isolated Hepatocytes . 401 Johan Hogberg 46. Discussion ............................................... 415 47. New Data Supporting an Obligatory Role for Lipid Peroxidation in Carbon Tetrachloride-Induced Loss of Aminopyrine Demethylase, Cytochrome P450, and Glucose-6-phosphatase ................... 417 Richard O. Recknagel, Eric A. Glende, Jr., and Andrew M. Hruszkewycz *Poster sessions. Contents xi 48. Discussion ............................................... 429 49. Binding of Haloalkanes to Liver Microsomes ..................... 431 Hartmut Uehleke 50. Discussion ............................................... 446 51. Degradation of Cytochrome P450 Heme and Lipid Peroxidation in Lead-Poisoned Rats* ....................................... 448 W. Penning and P. Scoppa VI. Reactive Intermediates in Carcinogenesis 52. The Effects of Microsomal Enzymes on Chemical Oncogenesis in Culture ................................................. 455 Stephen Nesnow and Charles Heidelberger 53. Discussion ............................................... 468 54. Role of Covalent Binding in Carcinogenicity ..................... 470 Peter Brookes 55. Discussion ............................................... 481 56. Interactions of Carcinogens with Human Cell DNA: Damage and Repair .................................................. 483 James D. Regan 57. Discussion ............................................... 492 58. The Origin, Present Status, and Trends of Toxicology: A Review of the Symposium in Turku, 1975 .................................. 493 Herbert Remmer Participants ................................................. 499 Index ...................................................... 507
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