Biological Reactive Intermediates—II Chemical Mechanisms and Biological Effects

In the summer of 1975 a small group of toxicologists, pathologists, biochemists and other scientists with closely related interests met at the University of Turku in Finland for two days to discuss what was, at that time, the rapidly emerging field of biological reactive intermediates. Biological reactive intermediates are the metabolic products of Xenobiotics chemicals which are chemically highly reactive and which appear to be largely responsible for the toxic and carcinogenic effects attributed to the parent compound. Furthermore, these effects are thought to be mediated by the covalent binding of reactive metabolites to critical cellular macromolecules such as proteins and nucleic acids. From the two days of intensive discussion at Turku came the first written report in this series (BIOLOGICAL REACTIVE INTERMEDIATES: FORMATION, TOXICITY AND INACTIVATION, D.J. Jollow, J.J. Kocsis, R. Snyder and H. Vainio, eds., Plenum Publishing Co., New York, 1977). Although the concepts of covalent binding and the adverse effects that may ensue were first proposed many years ago, the field developed rapidly during the early 1970's, mainly through the efforts of Professors E.C. and J.A. Miller of the University of Wisconsin, and the meeting in Turku summarized much that had been learned and pointed the way toward further studies that would be needed for our understanding of these phenomena. Indeed, progress in the study of biological reactive intermediates continued unabated and out of frequent communication among the participants of the Turku conference a rose the concept of continuing the discussion of this rapidly increasing body of knowledge in the form of a second conference to be followed by another publication summarizing the results presented at the meeting. As a result of considerable planning and discussion among M.W. Anders (USA), J.W. Bridges (UK), J.R. Gillette (USA), C.D. Klaassen (USA), J.J. Kocsis, (USA), D.B. Menzel (USA), M. Mercier (Belgium), R.A. Neal (USA), F. Oesch (BRD), S. Orrenius (Sweden), H. Remmer (BRD), M. Roberfroid (Belgium), H. Vainio (Finland) and C.M. Witmer (USA), acting 'as a committee under G.G. Gibson (UK), D.J. Jollow (USA), D.V. Parke (UK) and R. Snyder (USA), co-chairmen, THE SECOND INTERNATIONAL SYMPOSIUM ON BIOLOGICAL REACTIVE INTERMEDIATES was convened at the University of Surrey in the United Kingdom on July 14-17, 1980. This volume derives directly from the presentations at the symposium. The University of Surrey, which is located in Guildford, Surrey, provided a congenial atmosphere for this conference and we would like to take this opportunity to thank the local organizing committee and especially Dr. G. Gordon Gibson, for all their efforts in both scientific and social arrangements. Special thanks are extended also to the graduate students of the Biochemistry Department (especially Ms. Tricia Breacker and Mr. Paul Tamburini) and to the conference secretaries who unstintingly gave of their time in a variety of roles to ensure the smooth functioning of the symposium. We wish to acknowledge the tireless efforts of the distinguished scientists who agreed to chair the sessions of the symposium: A. Hildebrandt (BRD), H. Remmer (BRD), L. Goldberg (USA), S. Orrenius (Sweden), H. Uehleke (BRD), J.R. Gillette (USA), C. Netter (BRD), M. Mercier (Belgium), F. Oesch (BRD), E. Boyland (UK), J.E. Gibson (USA), C.D. Klaassen (USA) and J.W. Gorrod (UK). The mounting of a large scale international symposium is fraught with many impediments, not the least of which are the financial and logistical problems of assembling a group of internationally distinguished scientists in one place at the same time. Success in such endeavors requires concerned and active sponsors. The three sponsoring groups which combined to initiate this venture were the Toxicology Study Section of the Division of Research Grants, National Institutes of Health, Bethesda, MD, USA; the Department of Biochemistry of the University of Surrey, Guildford, Surrey, UK; and the College of Graduate Studies, Thomas Jefferson University, Philadelphia, PA, USA. We would also like to acknowledge the support of the Mobil Oil Company, the Rohm and Haas Co., the Dow Chemical Co., Hoffmann-LaRoche, Inc., the Celanese Corp., the Schering-Plough Corp., the Union Carbide Co., the Haskell Laboratories of E.I. DuPont de Nemours and Co., Inc., Proctor and Gamble, the Digital Equipment Corp., and the Drug Science Foundation of the Medical University of South Carolina. In keeping with the format established in the initial volume of BIOLOGICAL REACTIVE INTERMEDIATES, the editors did not present a verbatim reproduction of the discussions following the presentations, but rather condensed them to present the salient features. These condensations were prepared by B. Engelsberg, G. Kalf, J. Kocsis and C. Witmer, of Thomas Jefferson University, Philadelphia, PA, and S. Longacre of Medical College of South Carolina, Charleston, -SC. During the symposium we were saddened to learn of the death of Professor Otto Rosenthal of the University of Pennsylvania on July 14, 1980. Professor Rosenthal was a distinguished colleague and an active participant in the Turku symposium, as well as in many other international conferences. His initial recognition of the importance of cytochrome P-450 as the terminal heme protein in drug oxidations provided a foundation for our understanding of the role played by this enzyme system in the production of biological reactive intermediates. We, his friends and colleagues, will miss the many roles he played: researcher, scholar, scientific critic, philosopher, humorist and warm friend. Toxicology is by its very nature a multidisciplinary science. Thorough understanding of complex toxicological and oncological events requires communication among chemists and biologists from many fields and disciplines and a proper forum for the exchange of their ideas. Furthermore, no single country has a monopoly on scientific thought and achievement. In Guildford we had an international melting pot of scientific friends and colleagues freely communicating in the best traditions of science. We look forward to further progress in this field and to additional opportunities to present the work done in our laboratories to our colleagues for their information, for the opportunity for them to present constructive criticism and for all of us to continue to learn.