The International Symposium on Biological Reactive Intermediates

Robert Snyder,1

Department of Pharmacology and Toxicology, Ernest Mario School of Pharmacy, Rutgers University Environmental and Occupational Health Sciences Institute, 170 Frelinghuysen Road, Piscataway, New Jersey 08854

In his pioneering work entitled Detoxication Mechanisms: The Metabolism of Drugs and Allied Organic Compounds (John Wiley and Sons, New York, 1947), R. Tecwyn Williams wrote: "Although the term `detoxication' or `detoxication mechanism' implies some process or processes whereby toxicity in a compound is reduced or abolished, in its modern usage it includes not only changes involving a reduction in toxicity but also those involving an increase in toxicity." A number of mechanisms have been described by which the toxicity of a chemical is enhanced by metabolism, including the production of chemically reactive species called "biological reactive intermediates" or BRI. Following early reports by Miller and Miller (1966) relating the macromolecular covalent binding of carcinogen metabolites to carcinogenesis, a series of papers appeared in the Journal of Pharmacology and Experimental Therapeutics from the laboratory of B. B. Brodie and J. R. Gillette (Jollow et al., 1973Go; Mitchell et al., 1973aGo,bGo; Potter et al., 1973Go; Zampaglione et al., 1973Go) at the National Institutes of Health in Bethesda, Maryland that related the hepatotoxicity of acetaminophen and bromobenzene with the extent to which metabolites of these chemicals were found to be covalently bound to cellular proteins. Side by side with advances in our understanding of the metabolism of xenobiotics, the study of formation and toxicity of BRI has occupied mechanistic toxicologists for several decades, and the International Symposium on Biological Reactive Intermediates has been a significant medium for reporting, discussing, and disseminating the results of research on BRI.

The BRI symposia had their origins in the early 1970s when Professor J. J. Kocsis and I were engaged in a series of studies aimed at characterizing the association of benzene toxicity with benzene metabolism. We had observed that when radiolabeled benzene was administered to mice it was possible to detect covalent binding of benzene metabolites to proteins in many organs in the body including bone marrow, which is the target organ for benzene toxicity (Longacre et al., 1981Go; Snyder et al., 1978Go). While it seemed reasonable that there was an association between toxicity and covalent binding in bone marrow, the significance of covalent binding in other organs was less readily understandable. We decided to go to the experts on covalent binding and, accordingly, arranged for a liquid lunch in the bar of the old Marlborough Blenheim Hotel in Atlantic City at the April 1974 FASEB meetings. Jim Gillette and David Jollow represented the Brodie laboratory.

During intensive discussions, which were only occasionally interrupted by the bar man, we came to the conclusion that they knew little more about the significance of covalent binding than we did. It was suggested by Jim Miller (Miller and Miller, 1977Go) at the first BRI symposium that, following the initial enzymatic activation of chemicals, frequently by the mixed-function oxidases, some of the resulting metabolites were electrophilic and could bind chemically to nucleophilic sites on macromolecules, either locally or at remote sites. The outcome was a change in biological activity of the macromolecules resulting in toxic or carcinogenic responses. The degree of specificity to which alterations of macromolecules, cells, or organs resulted in disease processes was difficult to predict. Indeed it was recognized that covalent binding to some proteins might result in toxicity, whereas other protein binding might detoxify reactive molecules.

We recognized that there were others interested in this problem and guessed that they were equally in need of sharing their lack of understanding. The predictable result was that we decided to hold an international symposium to share our mutual ignorance, to console each other on our lack of appreciation of what was likely to be a significant biological mechanism, and to suggest further studies to clarify the problem.

The First International Symposium on Biological Reactive Intermediates (BRI I) was organized as a satellite meeting to the International Congress on Pharmacology in 1975 in Helsinki, Finland. Immediately following the termination of the Congress, approximately 100 of us boarded buses and were driven to Turku, a university town on the southwest coast of Finland. The meeting was held at the University and a young faculty member, Dr. Harri Vainio, acted as local chairperson. The development of the program and the organization of BRI-I was done by a committee consisting of J. F. Borzelleca, J. R. Gillette, O. Hänninen, D. J. Jollow, J. J. Kocsis, H. Remmer, R. Snyder, and H. Vainio, following programmatic input solicited from approximately 75 colleagues from around the world. BRI-I was a two-day meeting (July 26 and 27, 1975). Among the highlights of the meeting were the awarding of medals to B. B. Brodie, H. Remmer, and R. T. Williams, by Professor Kaarlo J. W. Hartiala, Chancellor of the University, a brilliant keynote presentation by Jim Miller, and an address by R. T. Williams describing his experiences during World War II when he was asked to study the metabolism of trinitrotoluene. The explosive nature of the substrate and its metabolites resulted in hazardous situations not related to the toxicity of the chemicals.

A few years following BRI-I we recognized that there was interest among our colleagues in a follow-up meeting. It should be emphasized that to this point there has never been a central organization that has run the BRI symposia. Kocsis, Jollow, Gillette, Vainio, and I organized the meeting with programmatic input from many people. Later Gordon Gibson and Glenn Sipes became part of the organizing committee and over the years many others have contributed. In discussions among the organizing committee we agreed that we should space these symposia at five-year intervals because we had no standing secretariat to supervise organization of an international meeting. We had to devote the time necessary to find a venue and a local chairperson, to organize a program, to raise funds, and to arrange for publication of the proceedings. Furthermore, we felt that by allowing sufficient time to elapse between symposia, we could insure that at each meeting we could present an entirely new series of subjects rather than receive an update on projects discussed at the previous meeting, which frequently occurs at annual or biannual meetings We began gathering groups to meet at the Society of Toxicology to make program suggestions, and these developed into a true program committee, which is currently chaired by Terrence Monks. The demand for continuing the series of symposia has resulted in the subsequent meetings. Table 1Go shows the host and local chairpersons, the location, and dates and titles of the publications for BRI-I to BRI-VI.


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TABLE 1 Historical Summary Biological Reactive Intermediates Symposia 1975–2000
 
Each symposium has had a central theme. The early symposia concentrated on production, inactivation, and toxic effects of specific reactive metabolites. We then moved to mechanistic studies and animal models for human diseases. The more recent meetings have focused on molecular and cellular mechanisms, and we have begun to explore the use of mechanistic data in risk assessment.

In each case, the proceedings were published by the Plenum Publishing Company, which is now Kluwer Academic/Plenum Publishers, to whom we are indebted for the high quality of the printed text. The plan has been for each invited speaker to submit a manuscript in camera-ready form. Speakers' expenses are partially reimbursed, the extent depending upon the success of fund raising efforts, provided that the speaker submits a manuscript. For example, for BRI-VI, resources came from NIEHS, USEPA, ATSDR/CDC, agencies of the French government, several universities, and a number of companies. Presenters of short communications may submit papers not to exceed four pages.

Looking back over the past 25+ years it appears that the BRI series, incubated in cocktails and devised in the old Marlborough Blenheim, was a good idea that has persisted. People frequently ask about when and where the next BRI will be held and volunteer to make presentations. My personal feeling about these meetings was expressed in the preface of an early volume: International cooperation and exchange of ideas should never be considered extraordinary. Communication is the life-blood 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.

NOTES

1 For correspondence via fax: (732) 445-0119. E-mail: rsnyder{at}eohsi.rutgers.edu. Back

REFERENCES

Jollow, D. J., Mitchell. J. R., Potter, W. Z., Davis, D. C., Gillette, J. R., and Brodie, B. B. (1973). Acetaminophen-induced hepatic necrosis: II. Role of covalent binding in vivo. J. Pharmacol. Exp. Ther. 187,195–202.[ISI][Medline]

Longacre, S. L., Kocsis, J. J., and Snyder, R. (1981). Influence of strain differences in mice on the metabolism and toxicity of benzene. Toxicol. Appl. Pharmacol. 60, 398–409.[ISI][Medline]

Miller, E. C., and Miller, J. A. (1966). Mechanisms of chemical carcinogenesis: Nature of proximate carcinogens and interactions with macromolecules. Pharmacol. Rev. 18,805–838.[ISI][Medline]

Miller, J. A., and Miller, E. C. (1977). The concept of reactive electrophilic metabolites in chemical carcinogenesis: Recent results with aromatic amines, safrole, and aflatoxin B1. In Biological Reactive Intermediates: Formation, Toxicity, and Inactivation (D. J. Jollow, J. J. Kocsis, R. Snyder, and H. Vainio, Eds.), pp. 6–24. Plenum Press, New York.

Mitchell, J. R., Jollow, D. J., Potter, W. Z., Davis, D. C., Gillette, J. R., and Brodie, B. B. (1973a). Acetaminophen-induced hepatic necrosis: I. Role of drug metabolism. J. Pharmacol. Exp. Ther. 187, 185–194.[ISI][Medline]

Mitchell, J. R., Jollow, D. J., Potter, W. Z., Gillette, J. R., and Brodie, B. B. (1973b). Acetaminophen-induced hepatic necrosis. IV. Protective role of glutathione. J. Pharmacol. Exp. Ther. 187,211–217.[ISI][Medline]

Potter, W. Z., Davis, D. C., Mitchell, J. R., Jollow, D. J., Gillette, J. R., and Brodie, B. B. (1973). Acetaminophen-induced hepatic necrosis: III. Cytochrome P-450-mediated covalent binding in vitro.J. Pharmacol. Exp. Ther. 187, 203– 210[ISI][Medline]

Snyder, R., Lee, E. W., and Kocsis, J. J. (1978). Binding of labeled benzene metabolites to mouse liver and bone marrow. Res. Commun. Chem. Pathol. Pharmacol. 20, 191–194.[ISI][Medline]

Zampaglione, N., Jollow, D. J., Mitchell, J. R., Stripp, B., Hamrick, M., and Gillette, J. R. (1973). Role of detoxifying enzymes in bromobenzene-induced liver necrosis. J. Pharmacol. Exp. Ther. 187, 218–277.[ISI][Medline]





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