Obituary pubs.acs.org/crt
encompassed a broad spectrum of topics related to the role of metabolic activation in foreign compound-mediated toxicity, and he published widely on compounds such as the fire retardant tris-(2,3-dibromopropyl)-phosphate (a long-standing collaboration with Erik Dybing), the abortifacient terpene (R)(+)-pulegone and its metabolite menthofuran, the carcinogenic hydrazine derivatives 1,2-dimethylhydrazine and procarbazine, the antiepileptic drug carbamazepine, the androgen receptor antagonist flutamide and analogues thereof, the endogenous estrogen 17β-estradiol, and, most recently, the anticancer dual kinase inhibitor lapatinib. However, Sid is perhaps best known for his seminal work on the bioactivation of acetaminophen to the transient intermediate, N-acetyl-para-benzoquinoneimine (NAPQI), which was first synthesized in his laboratory and reported in 1984 in what has become a classic publication in Proceedings of the National Academy of Sciences (USA). Using acetaminophen and its nonhepatotoxic isomer, 3′-hydroxyacetanilide, as model compounds, Sid went on to demonstrate that the two compounds differed significantly with respect to the pattern of cellular proteins which became alkylated following administration to animals; thus, while the reactive metabolite of acetaminophen bound covalently primarily to liver mitochondrial proteins, that of 3′-hydroxyacetanilide mainly targeted proteins in the endoplasmic reticulum and cytosol of liver cells, an important clue to the pronounced differences in hepatotoxic properties of these structurally very similar compounds. Sid’s group also demonstrated that NAPQI formed a previously unknown conjugate with glutathione (GSH), in which the GSH moiety was attached to the acetanilide ring system in the form of an ipso adduct, a potential transport form of the reactive quinoneimine itself. In addition to all of these projects, Sid also made important contributions to our understanding of basic aspects of cytochrome P450 catalysis, to the interaction of P450 with its cognate research partner, NADPH-cytochrome P450 reductase, and to the mechanism by which aromatase inhibitors act to block the formation of estrogenic steroids. Collectively, these scientific contributions have served to further our knowledge of the biochemical mechanisms by which a diverse array of therapeutic agents cause their toxic effects and thus have impacted the development of safer, more effective medicines. Not surprisingly, Sid’s research has been recognized both nationally and internationally in the form of numerous awards and honorary appointments. These include the John J. Abel Award in Pharmacology (1981), the Frank Blood Award in Toxicology (1983), the Sato Memorial International Award for Research from the Japanese Pharmaceutical Society (1992), and a Wellcome Visiting Professorship in the Basic Medical Sciences (1998). He spent a year with Peter Moldéus as a Visiting Professor in the Department of Toxicology at the Karolinska Institute in Stockholm, Sweden (1985−1986), and the first half of 2010 as a Visiting Professor at Imperial College,
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idney (Sid) D. Nelson, an internationally renowned educator, academic administrator, and pioneer in the study of the role of chemically reactive metabolites in drug-induced toxicity, died suddenly at his home in Everett, Washington, on December 9, 2011. He was 66 years old. Sid was born on August 18, 1945, in Seattle, Washington. He was raised in Seattle and attended the University of Washington where he graduated in 1968 with a B.S. degree in Pharmacy. Following military service in the U.S. Army Medical Corps (1968−1970), Sid returned to graduate school where he conducted research under the late Professor Bill Trager, initially at the University of Washington and subsequently at the University of California, San Francisco from which he received a Ph.D. degree in Pharmaceutical Chemistry in 1974. Sid then moved to the National Institutes of Health in Bethesda, Maryland, where he was a Staff Fellow in the PharmacologyToxicology Research Associate Training Program at NIGMS (1974−1976) and later in the Laboratory of Chemical Pharmacology at the NHLBI (1976−1977). It was during this period that Sid, working with a cadre of eminent researchers including Jim Gillette, Jerry Mitchell, Lance Pohl, Jack Hinson, Erik Dybing, and others, developed an interest in the role of metabolic activation in the serious toxicities of certain therapeutic agents. Many contemporary concepts of reactive metabolite formation as they relate to drug-induced liver injury were developed during these productive years, and Sid was a coauthor on numerous publications on the bioactivation of drugs such as acetaminophen, phenacetin, isoniazid, iproniazid, chloramphenicol, and analogues thereof. Much of this work was made possible by the recent advent of more capable mass spectrometric techniques, augmented by the availability of stable isotope tracer methodology, and Sid’s work effectively exploited these powerful new approaches for the study of short-lived, biological reactive intermediates. Sid’s love of the Pacific Northwest brought him back to Seattle in 1977, where he took up an appointment as Assistant Professor of Medicinal Chemistry in the School of Pharmacy at his alma mater, the University of Washington. It was here that Sid remained for the duration of his remarkable career, progressing through the ranks to Associate (1980) and Full Professor (1983) of Medicinal Chemistry and serving as Dean of the School from 1995 to 2008. During that time, his research © 2011 American Chemical Society
Received: December 14, 2011 Accepted: December 14, 2011 Published: December 23, 2011 2
dx.doi.org/10.1021/tx200544j | Chem. Res. Toxicol. 2012, 25, 2−3
Chemical Research in Toxicology
Obituary
London, in Jeremy Nicholson’s laboratory. At the time of his death, Sid also was a Visiting Professor at the National University of Singapore. In addition to his numerous research accomplishments, Sid was an outstanding educator in a classroom setting, for which he also received a number of teaching awards from the University of Washington. Some 26 graduate students received their Ph.D. degrees under Sid’s guidance, and a total of 15 postdoctoral fellows and 9 visiting scientists spent varying periods of time in his laboratory. He was an active member of several scientific societies, including the American Association for the Advancement of Science, the American Chemical Society Division of Medicinal Chemistry, the American Society for Pharmacology and Experimental Therapeutics, the Society of Toxicology, the International Society for the Study of Xenobiotics, and the American Society for Mass Spectrometry, as well as a number of professional pharmacy organizations. Sid was a member of the Pharmacology Study Section, NIH (1986−1990), the Pharmacological Sciences Review Committee, NIH (1992−1996), and served on several editorial advisory boards and as a consultant to the pharmaceutical industry in the areas of drug metabolism and toxicology. Sid is survived by his wife, Joan, children Devon, John, Jens, Noel, Tricia, Andi, and Steen, and grandchildren Haily, Max, Grace, Paige, and Sofia, to whom we extend our heartfelt condolences. Sid’s death is a major loss to our School, the University of Washington, academic pharmacy nationally, and the global scientific community. It was an honor to know him as an educator, mentor, colleague, and friend. He will be sorely missed.
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