Most chemicals, including drugs, are transformed in animals and humans to a variety of metabolites. Although many of these metabolites are physiologically inactive, s ome are active either therapeutically or toxicologically. Research in our laboratory is focused primarily on the elucidation of chemical and biochemical mechanisms by which highly reactive, toxic metabolites are formed, on their structural identification, and on characterization of their interactions with cellular macromolecules, such as proteins and DNA. We hope that knowledge of pathogenic mechanisms will lead to the introduction of safer drugs and other chemicals. We are also investigating the effects of protein-protein interactions on structure/function relationships of drug metabolizing enzymes.

During the course of our investigation, we often synthesize analogs of the chemicals to probe the sites at which tissue enzymes react with the chemical to form toxic metabolites. For example, we have prepared methylated analogs of the widely used analgesic, acetaminophen, to determine which of several possible mechanisms is most responsible for the propensity of this drug to cause liver damage when it is ingested in large doses. We have prepared deuterated analogs of a natural product terpene, which has been used to induce abortions, to identify the sites of enzymic oxidation of the compound to form a liver and lung toxin. Genomic, proteomic and metabonomic studies help us better define cellular pathways involved in drug toxicities and generate new testable hypotheses.

Finally, we are using the knowledge obtained from such studies to synthesize new chemicals and drugs that are less toxic or are directed to damage-selected enzyme targets in order to achieve a beneficial therapeutic action. For example, we have synthesized some thiol analogs of a steroid that form reactive metabolites at a selected site to chemically inactivate an enzyme that is important in the growth of some breast cancers.

In all of our studies, we utilize a combination of sophisticated, state-of-the-art analytical techniques (IR, UV, NMR, GC, HPLC, MS) to characterize our synthetic products and to both qualitatively and quantitatively assay metabolites and modifications to proteins.

Recent Publications

• Ho HK, Hu ZH, Tzung SP, Hockenbery DM, Fausto N, Nelson SD, and Bruschi SA. "BCL-xL Overexpression Effectively Protects Against Tetrafluoroethylcysteine-induced Intramitochondrial Damage and Cell Death." Biochem Pharmacol. 69:147-157 (2005).


• Wen B, Doneanu CE, Gartner CA, Roberts AG, Atkins WM, and Nelson SD. "Fluorescent Photoaffinity Labeling of Cytochrome P450 3A4 by Lapachenole: Identification of Modification Sites by Mass Spectrometry." Biochemistry 44:1833-1845 (2005).


• Gartner CA, Wen B, Wan J, Becker RS, Jones G, Gygi SP, and Nelson SD. "Photochromic Agents as Tools for Protein Structure Study: Lapachenole is a Photoaffinity Ligand of Cytochrome P450 3A4." Biochemistry 44:1846-1855 (2005).


• Ho HK, White CC, Fernandez C, Fausto N, Kavanaugh TS, Nelson SD, and Bruschi SA. "Nrf2 Activation Involves An Oxidative-Stress Independent Pathway in Tetrafluoroethycysteine-Induced Cytotoxicity." Toxicol Sci. 86:354-364 (2005).


• Welch KD, Wen B, Goodlett DR, Yi EC, Lee H, Reilly TP, Nelson SD, and Pohl LR. "Proteomic Identification of Potential Susceptibility Factors in Drug-Induced Liver Disease." Chem Res Toxicol. 18:924-933 (2005).


• Regal KA, Kunze KL, Peter RM and Nelson SD. "Oxidation of Caffeine by CYP1A2: Isotope Effects and Metabolic Switching." Drug Metab Dispos. 33:1837-1844 (2005).


• Cameron MD, Wen B, Allen KE, Roberts AG, Schuman JT, Campbell AP, Kunze KL, and Nelson SD. "Cooperative Binding of Midazolam with Testosterone and ±-Naphthoflavone within the CYP3A4 Active Site: A NMR T1 Paramagnetic Relaxation Study." Biochemistry 44:14143-14151 (2005).


• Wen B, Doneanu CE, Lampe JN, Roberts AG, Atkins WM and Nelson SD. Nelson: "Probing the CYP3A4 Active Site by Cysteine Scanning Mutagenesis and Photoaffinity Labeling." Arch Biochem Biophys. 444:100-111 (2005).


• Gao Q, Xue S, Doneanu CE, Shaffer SA, Goodlett DR, and Nelson SD. "Pro-CrossLink - A Software Tool for Protein Crosslinking and Mass Spectrometry." Anal Chem. 78:2145-2149 (2006).


• Ho HK, Jia Y, Coe KJ, Gao Q, Doneanu CE, Hu Z, Bammler TK, Beyer RP, Fausto N, Bruschi SA, and Nelson SD. "Cytosolic Heat Shock Proteins and Heme Oxygenase-1 are Preferentially Induced in Response to Specific and Localized Intramitochondrial Damage by Tetrafluoroethylcysteine." Biochem Pharmacol. 72:80-90 (2006).


• Coe KJ, Nelson SD, Ulrich RG, He Y, Dai X, Cheng O, Caguyong M, Roberts CJ, and Slatter JG. "Profiling the Hepatic Effects of Flutamide in Rats: A Microarray Comparison with Classical Aryl Hydrocarbon Receptor Ligands and Atypical CYP1A Inducers." Drug Metab Dispos. 34:1266-1275 (2006).


• Gao Q, Doneanu CE, Shaffer SA, Adman ET, Goodlett DR, and Nelson SD. "Identification of the Interactions Between Cytochrome P450 2E1 and Cytochrome b5 by Mass Spectrometry and Site-Directed Mutagenesis." J Biol Chem. 281:20404-20417 (2006).


• Wen B, Lampe JN, Roberts AG, Atkins WM, Rodrigues AD, and Nelson SD. "Cysteine 98 in CYP3A4 Contributes to Conformational Integrity Required for P450 Interaction with CYP Reductase." Arch Biochem Biophys. 454:42-54 (2006).


• Mutlib A, Jinag P, Atherton J, Obert L, Kostrubsky S, Madore S, and Nelson SD. "Identification of Potential Genomic Biomarkers of Hepatotoxicity Caused by Reactive Metabolites of N-Methylformamide: Application of Stable Isotope Labeled Compounds in Toxicogenomic Studies." Chem Res Toxicol. 19:1270-1283 (2006).


• Coe KJ, Jia Y, Ho HK, Rademacher P, Bammler TK, Beyer RP, Farin FM, Woodke L, Plymate SR, Fausto N, and Nelson SD. "Comparison of the Cytotoxicity of the Nitroaromatic Drug Flutamide to Its Cyano Analogue in the Hepatocyte Cell Line TAMH: Evidence for Complex I Inhibition and Mitochondrial Dysfunction Using Toxicogenomic Screening." Chem Res Toxicol. 20:1277-1290 (2007).


• Cameron MD, Wen B, Roberts AG, Atkins WM, Campbell AP, and Nelson SD. "Cooperative Binding of Acetaminophen and Caffeine within the P450 3A4 Active Site." Chem Res Toxicol. 20:1434-1441 (2007).


• Kostrubsky SE, Strom SC, Ellis E, Nelson SD, and Mutlib AE. "Transport, Metabolism, and Hepatotoxicity of Flutamide, Drug-Drug Interaction with Acetaminophen Involving Phase I and Phase II Metabolites." Chem Res Toxicol. 20:1503-1512 (2007).


• Harrelson JP, Henne KR, Alonso DOV, and Nelson SD. "A Comparison of Substrate Dynamics in Human CYP2E1 and CYP2A6." Biochem Biophys Res Commun. 352:843-849 (2007).


• Harrelson JP, Atkins WM, and Nelson SD. "Multiple Ligand Binding in CYP2A6: Probing Mechanisms of Cytochrome P450 Cooperativity by Assessing Substrate Dynamics." Biochemistry 47:2978-2988 (2008).


• Wen B, Ma L, Nelson SD, and Zhu M. "High-Throughput Screening and Characterization of Reactive Metabolites Using Polarity Switching of Hybrid Triple Quadrupole Linear Ion Trap Mass Spectrometry." Anal Chem. 80:1788-1799 (2008).


• Gao Q, Xue S, Shaffer SA, Doneanu CE, Goodlett DR, and Nelson SD. "Minimize the Detection of False Positives by the Software Program Detectshift for ¹⁸O-labeled Cross-Linked Peptide Analysis." Eur J Spectrom. 14:275-280 (2008).


• Wen B, Coe KJ, Rademacher P, Fitch WL, Monshouwer M, and Nelson SD. "Comparison of in Vitro Bioactivation of Flutamide and Its Cyano Analogue: Evidence for Reductive Activation by Human NADPH:Cytochrome P450 Reductase." Chem Res Toxicol. 21:2393-2406 (2008).

Recent Book Chapters and Review Articles:

• Nelson SD. "Drug-Drug Interactions: Toxicological Perspectives." In Drug-Drug Interactions: From Basic Pharmacokinetic Concepts to Marketing Issues, A.D. Rodrigues, ed., Marcel Dekker, Inc., New York, 2001, pp. 585-604.


• Nelson SD. "Structure Toxicity Relationships - How Useful Are They in Predicting Toxicities of New Drugs?" In Biological Reactive Intermediates VI, P.M. Dansette et al., eds., Kluwer Academic/Plenum Publishers, New York, 2001, pp. 33-43.


• Nelson SD. "Molecular Mechanisms of Adverse Drug Reactions." Current Therapeutic Research 62:885-899 (2001).


• Gartner CA and Nelson SD. "Aromatase, the Enzyme Responsible for Estrogen Biosynthesis." In Wiley Encyclopedia of Molecular Medicine, John Wiley and Sons, Inc., New York, 2002, pp. 253-225.


• Nelson SD and Bruschi SA. "Mechanisms of Acetaminophen-Induced Liver Disease." In Drug-Induced Liver Disease, N. Kaplowitz and L. DeLeve, eds., Marcel Dekker, Inc., New York, 2002, pp. 287-326.


• Nelson SD and Trager WF. "The Use of Deuterium Isotope Effects to Probe the Active Site Properties, Mechanism of Cytochrome P450-Catalyzed Reactions, and Mechanisms of Metabolically Dependent Toxicity." Drug Metab. Dispos. 31:1481-1498 (2003).


• Nelson SD and Bruschi SA. "Mechanisms of Acetaminophen-Induced Liver Disease." In Drug-Induced Liver Disease, Second Edition, N. Kaplowitz and L. DeLeve, eds. Informa Healthcare, USA Inc., New York, 2007, pp. 353-388.


• Nelson SD. "Drug-Drug Interactions: Toxicological Perspectives." In Drug-Drug Interactions, Second Edition, A.D. Rodrigues, ed. Informa Healthcare, USA Inc., New York, 2008.


• Nelson SD. "The Accidental Dean." In The Dean's Compass: Practical Advice for Achieving Excellence. P.A. Chase, B.E. Hayes and V.A. Yanchik, eds. AACP Press, Alexandria, 2008.