Research Focus Area:
Health Disparities, Treatment, Informatics, Detection, Carcinogenesis, Diagnosis/ Prognosis
Type of Research:
Research Interest Statement:
Integrating datamining, modeling and experimental approaches to develop safer targeted cancer therapeutics Recent advances in targeted cancer therapeutics boast superior health outcomes relative to traditional chemotherapy drugs; however, hepatotoxicity poses a major clinical concern for patients undergoing treatment with these revolutionary drugs. Drug metabolism plays a central role in toxicological mechanisms and thus, my research focuses on assessing clearance and bioactivation of drugs and subsequent biological, pharmacological and toxicological impacts on human health. In practice, my group integrates and leverages powerful analytical, biochemical, and computational tools to identify and quantitate small molecules including drugs present in biological samples and generated from metabolic reactions. Next, we correlate findings to biological activity and in vivo outcomes such as liver toxicity to establish toxicological mechanisms and the factors impacting those outcomes. Knowledge gained from these studies will aid in the design and use of safer targeted cancer therapeutics by minimizing associated toxicities that limit their use in the clinic.
Schleiff MA, Crosby S, Blue M, [et al., including Miller GP]. CYP2C9 and 3A4 play opposing roles in bioactivation and detoxification of diphenylamine NSAIDs. Biochemical pharmacology. 2021 194:114824. PMID: 34748821.
Cui H, Carlson AS, Schleiff MA, [et al., including Miller GP]. 4-Methyl-1,2,3-Triazoles as N-Acetyl-Lysine Mimics Afford Potent BET Bromodomain Inhibitors with Improved Selectivity. Journal of medicinal chemistry. 2021. PMID: 34236185.
Datta A, Flynn NR, Barnette DA, [et al., including Miller GP]. Machine learning liver-injuring drug interactions with non-steroidal anti-inflammatory drugs (NSAIDs) from a retrospective electronic health record (EHR) cohort. PLoS computational biology. 2021 17(7):e1009053. PMID: 34228716.
Flynn NR, Ward MD, Schleiff MA, [et al., including Miller GP]. Bioactivation of Isoxazole-Containing Bromodomain and Extra-Terminal Domain (BET) Inhibitors. Metabolites. 2021 11(6). PMID: 34203690. PMCID: PMC8232216.
Schleiff MA, Payakachat S, Schleiff BM, [et al., including Miller GP]. Impacts of diphenylamine NSAID halogenation on bioactivation risks. Toxicology. 2021:152832. PMID: 34107285.
Khojasteh SC, Argikar UA, Driscoll JP, [et al., including Miller GP]. Novel Advances in Biotransformation and Bioactivation Research - 2020 year in review. Drug metabolism reviews. 2021:1-91. PMID: 33910427.
Pouncey DL, Barnette DA, Sinnott RW, [et al., including Miller GP]. Discovery of Novel Reductive Elimination Pathway for 10-Hydroxywarfarin. Frontiers in pharmacology. 2021 12:805133. PMID: 35095511. PMCID: PMC8793337.
Barnette DA, Schleiff MA, Datta A, [et al., including Miller GP]. Meloxicam methyl group determines enzyme specificity for thiazole bioactivation compared to sudoxicam. Toxicology letters. 2020 338:10-20. PMID: 33253783.
Schleiff MA, Flynn NR, Payakachat S, [et al., including Miller GP]. Significance of Multiple Bioactivation Pathways for Meclofenamate as Revealed through Modeling and Reaction Kinetics. Drug metabolism and disposition: the biological fate of chemicals. 2020. PMID: 33239334.
Pinson AO, Pouncey DL, Schleiff MA, [et al., including Miller GP]. Significance of Competing Metabolic Pathways for 5F-APINACA Based on Quantitative Kinetics. Molecules (Basel, Switzerland). 2020 25(20). PMID: 33092129. PMCID: PMC7587938.
Khojasteh SC, Driscoll JP, Jackson KD, [et al., including Miller GP]. Novel advances in biotransformation and bioactivation research-2019 year in review. Drug metabolism reviews. 2020 52(3):333-365. PMID: 32645275.
Barnette DA, Schleiff MA, Osborn LR, [et al., including Miller GP]. Dual mechanisms suppress meloxicam bioactivation relative to sudoxicam. Toxicology. 2020 440:152478. PMID: 32437779.
Barnette DA, Davis MA, Flynn N, [et al., including Miller GP]. Comprehensive kinetic and modeling analyses revealed CYP2C9 and 3A4 determine terbinafine metabolic clearance and bioactivation. Biochemical pharmacology. 2019 170:113661. PMID: 31605674. PMCID: PMC6905088.
Matlock MK, Tambe A, Elliott-Higgins J, [et al., including Miller GP]. A Time-Embedding Network Models the Ontogeny of 23 Hepatic Drug Metabolizing Enzymes. Chemical research in toxicology. 2019 32(8):1707-1721. PMID: 31304741. PMCID: PMC6933754.
Davis MA, Barnette DA, Flynn NR, [et al., including Miller GP]. CYP2C19 and 3A4 Dominate Metabolic Clearance and Bioactivation of Terbinafine Based on Computational and Experimental Approaches. Chemical research in toxicology. 2019 32(6):1151-1164. PMID: 30925039. PMCID: PMC6692898.
Khojasteh SC, Bumpus NN, Driscoll JP, [et al., including Miller GP]. Biotransformation and bioactivation reactions - 2018 literature highlights. Drug metabolism reviews. 2019 51(2):121-161. PMID: 31170851.
Kim SY, Kang JY, Yun CH, [et al., including Miller GP]. Regioselectivity significantly impacts microsomal glucuronidation efficiency of R/S-6, 7-, and 8-hydroxywarfarin. Xenobiotica; the fate of foreign compounds in biological systems. 2019 49(4):397-403. PMID: 29543105.
Freyaldenhoven S, Li Y, Kocabas AM, [et al., including Miller GP]. Withdrawal: The role of ERp44 in maturation of serotonin transporter protein. The Journal of biological chemistry. 2019 294(1):70. PMID: 30610126. PMCID: PMC6322887.
Pouncey DL, Hartman JH, Moore PC, [et al., including Miller GP]. Novel isomeric metabolite profiles correlate with warfarin metabolism phenotype during maintenance dosing in a pilot study of 29 patients. Blood coagulation & fibrinolysis : an international journal in haemostasis and thrombosis. 2018 29(7):602-612. PMID: 30334816.
Barnette DA, Davis MA, Dang NL, [et al., including Miller GP]. Lamisil (terbinafine) toxicity: Determining pathways to bioactivation through computational and experimental approaches. Biochemical pharmacology. 2018 156:10-21. PMID: 30076845. PMCID: PMC6188815.
Khojasteh SC, Miller GP, Mitra K, Rietjens IMCM. Biotransformation and bioactivation reactions - 2017 literature highlights *. Drug metabolism reviews. 2018 50(3):221-255. PMID: 29954222.
Dang NL, Hughes TB, Miller GP, Swamidass SJ. Computationally Assessing the Bioactivation of Drugs by N-Dealkylation. Chemical research in toxicology. 2018 31(2):68-80. PMID: 29355304. PMCID: PMC5871345.
Barnette DA, Johnson BP, Pouncey DL, [et al., including Miller GP]. Stereospecific Metabolism of R- and S-Warfarin by Human Hepatic Cytosolic Reductases. Drug metabolism and disposition: the biological fate of chemicals. 2017 45(9):1000-1007. PMID: 28646078. PMCID: PMC5539582.
Khojasteh SC, Rietjens IMCM, Dalvie D, Miller G. Biotransformation and bioactivation reactions - 2016 literature highlights. Drug metabolism reviews. 2017 49(3):285-317. PMID: 28468514.
Dang NL, Hughes TB, Miller GP, Swamidass SJ. Computational Approach to Structural Alerts: Furans, Phenols, Nitroaromatics, and Thiophenes. Chemical research in toxicology. 2017 30(4):1046-1059. PMID: 28256829. PMCID: PMC5871347.
Hartman JH, Miller GP, Caro AA, [et al.]. 1,3-Butadiene-induced mitochondrial dysfunction is correlated with mitochondrial CYP2E1 activity in Collaborative Cross mice. Toxicology. 2017 378:114-124. PMID: 28082109. PMCID: PMC5319481.
Hartman JH, Miller GP, Meyer JN. Toxicological Implications of Mitochondrial Localization of CYP2E1. Toxicology research. 2017 6(3):273-289. PMID: 28989700. PMCID: PMC5627779.
Hughes TB, Dang NL, Miller GP, Swamidass SJ. Modeling Reactivity to Biological Macromolecules with a Deep Multitask Network. ACS central science. 2016 2(8):529-37. PMID: 27610414. PMCID: PMC4999971.
Bostian AC, Maddukuri L, Reed MR, [et al., including Miller GP]. Kynurenine Signaling Increases DNA Polymerase Kappa Expression and Promotes Genomic Instability in Glioblastoma Cells. Chemical research in toxicology. 2016 29(1):101-8. PMID: 26651356. PMCID: PMC4718841.
Hartman JH, Martin HC, Caro AA, [et al., including Miller GP]. Subcellular localization of rat CYP2E1 impacts metabolic efficiency toward common substrates. Toxicology. 2015 338:47-58. PMID: 26463279. PMCID: PMC4658230.
Hartman JH, Letzig LG, Roberts DW, [et al., including Miller GP]. Cooperativity in CYP2E1 metabolism of acetaminophen and styrene mixtures. Biochemical pharmacology. 2015 97(3):341-9. PMID: 26225832. PMCID: PMC5584065.
Hughes TB, Miller GP, Swamidass SJ. Modeling Epoxidation of Drug-like Molecules with a Deep Machine Learning Network. ACS central science. 2015 1(4):168-80. PMID: 27162970. PMCID: PMC4827534.