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Applying Mechanisms of Chemical Toxicity to Predict Drug Safety

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Department of Biochemistry and Center in Molecular Toxicology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232-0146, and Drug Safety and Metabolism, Schering-Plough Research Institute, Kenilworth, New Jersey 07033-0530
Cite this: Chem. Res. Toxicol. 2007, 20, 3, 344–369
Publication Date (Web):February 16, 2007
https://doi.org/10.1021/tx600260a
Copyright © 2007 American Chemical Society
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    Abstract

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    Toxicology can no longer be used only as a science that reacts to problems but must be more proactive in predicting potential human safety issues with new drug candidates. Success in this area must be based on an understanding of the mechanisms of toxicity. This review summarizes and extends some of the concepts of an American Chemical Society ProSpectives meeting on the title subject held in June 2006. One important area is the discernment of the exact nature of the most common problems in drug toxicity. Knowledge of chemical structure alerts and relevant biological pathways are important. Biological activation to reactive products and off-target pharmacology are considered to be major contexts of drug toxicity, although defining exactly what the contributions are is not trivial. Some newer approaches to screening for both have been developed. A goal in predictive toxicology is the use of in vitro methods and database development to make predictions concerning potential modes of toxicity and to stratify drug candidates for further development. Such predictions are desirable for several economic and other reasons but are certainly not routine yet. However, progress has been made using several approaches. Some examples of the application of studies of wide-scale biological responses are now available, with incorporation into development paradigms.

    *

     To whom correspondence should be addressed:  Tel:  (615) 322-2261. Fax:  (615) 322-3141. E-mail:  [email protected].

    †

     Vanderbilt University.

    ‡

     Schering-Plough Research Institute.

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    61. Shanshan Huang, Kairui Feng, Yujie Ren. Molecular modelling studies of quinazolinone derivatives as MMP-13 inhibitors by QSAR, molecular docking and molecular dynamics simulations techniques. MedChemComm 2019, 10 (1) , 101-115. https://doi.org/10.1039/C8MD00375K
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    64. Parimal Pande, Melissa Giambalvo, Zimei Huang. Complementing preclinical safety assessments through genomic analyses. Current Opinion in Toxicology 2018, 11-12 , 59-66. https://doi.org/10.1016/j.cotox.2019.01.002
    65. Takayuki Amano, Tatsuki Fukami, Takuo Ogiso, Daisuke Hirose, Jeffrey P. Jones, Tsuyoshi Taniguchi, Miki Nakajima. Identification of enzymes responsible for dantrolene metabolism in the human liver: A clue to uncover the cause of liver injury. Biochemical Pharmacology 2018, 151 , 69-78. https://doi.org/10.1016/j.bcp.2018.03.002
    66. Nicholas D. Anastas, John Leazer, Michael A. Gonzalez, Stephen C. DeVito. Expanding Rational Molecular Design beyond Pharma: Metrics to Guide Safer Chemical Design. 2018, 29-48. https://doi.org/10.1002/9783527628698.hgc125
    67. B.K. Petroff, P. Basu. Ovarian Metabolism of Xenobiotics. 2018, 495-506. https://doi.org/10.1016/B978-0-12-801238-3.02155-3
    68. Mercedes Barzi, Francis P. Pankowicz, Barry Zorman, Xing Liu, Xavier Legras, Diane Yang, Malgorzata Borowiak, Beatrice Bissig-Choisat, Pavel Sumazin, Feng Li, Karl-Dimiter Bissig. A novel humanized mouse lacking murine P450 oxidoreductase for studying human drug metabolism. Nature Communications 2017, 8 (1) https://doi.org/10.1038/s41467-017-00049-x
    69. Zhengyu Wang, Xiaofan Shi, Huan Zhang, Liang Yu, Yanhua Cheng, Hefeng Zhang, Huibin Zhang, Jinpei Zhou, Jing Chen, Xu Shen, Wenhu Duan. Discovery of cycloalkyl-fused N-thiazol-2-yl-benzamides as tissue non-specific glucokinase activators: Design, synthesis, and biological evaluation. European Journal of Medicinal Chemistry 2017, 139 , 128-152. https://doi.org/10.1016/j.ejmech.2017.07.051
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    78. Denis M. Grant. Arylamine N ‐Acetyltransferases. 2016, 1-29. https://doi.org/10.1002/9780470921920.edm144
    79. Dan Xu, Gary Peltz. Can Humanized Mice Predict Drug “Behavior” in Humans?. Annual Review of Pharmacology and Toxicology 2016, 56 (1) , 323-338. https://doi.org/10.1146/annurev-pharmtox-010715-103644
    80. Aki Kohyama, Michihiro Fukuda, Shunsuke Sugiyama, Hiroyuki Yamakoshi, Naoki Kanoh, Chikashi Ishioka, Hiroyuki Shibata, Yoshiharu Iwabuchi. Reversibility of the thia-Michael reaction of cytotoxic C 5 -curcuminoid and structure–activity relationship of bis-thiol-adducts thereof. Organic & Biomolecular Chemistry 2016, 14 (45) , 10683-10687. https://doi.org/10.1039/C6OB01771A
    81. Dong-Myung Kim, Hanna Kim, Ji-Hyun Yeon, Ju-Hee Lee, Han-Oh Park. Identification of a Mitochondrial DNA Polymerase Affecting Cardiotoxicity of Sunitinib Using a Genome-Wide Screening on S. pombe Deletion Library. Toxicological Sciences 2016, 149 (1) , 4-14. https://doi.org/10.1093/toxsci/kfv210
    82. Stefan O. Mueller, André Guillouzo, Philip G. Hewitt, Lysiane Richert. Drug biokinetic and toxicity assessments in rat and human primary hepatocytes and HepaRG cells within the EU-funded Predict-IV project. Toxicology in Vitro 2015, 30 (1) , 19-26. https://doi.org/10.1016/j.tiv.2015.04.014
    83. Toni Lassila, Timo Rousu, Sampo Mattila, Christophe Chesné, Olavi Pelkonen, Miia Turpeinen, Ari Tolonen. Formation of GSH-trapped reactive metabolites in human liver microsomes, S9 fraction, HepaRG-cells, and human hepatocytes. Journal of Pharmaceutical and Biomedical Analysis 2015, 115 , 345-351. https://doi.org/10.1016/j.jpba.2015.07.020
    84. Xinkun Ren, Jake A. Yorke, Emily Taylor, Ting Zhang, Weihong Zhou, Luet Lok Wong. Drug Oxidation by Cytochrome P450 BM3 : Metabolite Synthesis and Discovering New P450 Reaction Types. Chemistry – A European Journal 2015, 21 (42) , 15039-15047. https://doi.org/10.1002/chem.201502020
    85. Xing Liu, Yuanfu Lu, Xinfu Guan, Bingning Dong, Hemantkumar Chavan, Jin Wang, Yiqing Zhang, Partha Krishnamurthy, Feng Li. Metabolomics reveals the formation of aldehydes and iminium in gefitinib metabolism. Biochemical Pharmacology 2015, 97 (1) , 111-121. https://doi.org/10.1016/j.bcp.2015.07.010
    86. Mark P Grillo. Detecting reactive drug metabolites for reducing the potential for drug toxicity. Expert Opinion on Drug Metabolism & Toxicology 2015, 11 (8) , 1281-1302. https://doi.org/10.1517/17425255.2015.1048222
    87. Aki Kohyama, Hiroyuki Yamakoshi, Shoko Hongo, Naoki Kanoh, Hiroyuki Shibata, Yoshiharu Iwabuchi. Structure-Activity Relationships of the Antitumor C5-Curcuminoid GO-Y030. Molecules 2015, 20 (8) , 15374-15391. https://doi.org/10.3390/molecules200815374
    88. Frank J Gonzalez, Zhong-Ze Fang, Xiaochao Ma. Transgenic mice and metabolomics for study of hepatic xenobiotic metabolism and toxicity. Expert Opinion on Drug Metabolism & Toxicology 2015, 11 (6) , 869-881. https://doi.org/10.1517/17425255.2015.1032245
    89. Johannes Kirchmair, Andreas H. Göller, Dieter Lang, Jens Kunze, Bernard Testa, Ian D. Wilson, Robert C. Glen, Gisbert Schneider. Predicting drug metabolism: experiment and/or computation?. Nature Reviews Drug Discovery 2015, 14 (6) , 387-404. https://doi.org/10.1038/nrd4581
    90. Douglas A. Keller, Richard J. Brennan, Karen L. Leach. Clinical and Nonclinical Adverse Effects of Kinase Inhibitors. 2015, 365-400. https://doi.org/10.1002/9783527673643.ch16
    91. Amit S. Kalgutkar, Deepak Dalvie. Predicting Toxicities of Reactive Metabolite–Positive Drug Candidates. Annual Review of Pharmacology and Toxicology 2015, 55 (1) , 35-54. https://doi.org/10.1146/annurev-pharmtox-010814-124720
    92. Deepak Dalvie, Amit S. Kalgutkar, Weichao Chen. Practical approaches to resolving reactive metabolite liabilities in early discovery. Drug Metabolism Reviews 2015, 47 (1) , 56-70. https://doi.org/10.3109/03602532.2014.984813
    93. Yun-Ping Lim, Ching-Hao Cheng, Wei-Cheng Chen, Shih-Yu Chang, Dong-Zong Hung, Jih-Jung Chen, Lei Wan, Wei-Chih Ma, Yu-Hsien Lin, Cing-Yu Chen, Tsuyoshi Yokoi, Miki Nakajima, Chao-Jung Chen. Allyl isothiocyanate (AITC) inhibits pregnane X receptor (PXR) and constitutive androstane receptor (CAR) activation and protects against acetaminophen- and amiodarone-induced cytotoxicity. Archives of Toxicology 2015, 89 (1) , 57-72. https://doi.org/10.1007/s00204-014-1230-x
    94. Peter Imming. Medicinal Chemistry. 2015, 3-13. https://doi.org/10.1016/B978-0-12-417205-0.00001-8
    95. Anne-Christine Macherey, Patrick M. Dansette. Biotransformations Leading to Toxic Metabolites. 2015, 585-614. https://doi.org/10.1016/B978-0-12-417205-0.00025-0
    96. Ana Carolina Valencia-Olvera, Julio Morán, Rafael Camacho-Carranza, Oscar Prospéro-García, Jesús Javier Espinosa-Aguirre. CYP2E1 induction leads to oxidative stress and cytotoxicity in glutathione-depleted cerebellar granule neurons. Toxicology in Vitro 2014, 28 (7) , 1206-1214. https://doi.org/10.1016/j.tiv.2014.05.014
    97. Shyam Sundhar Bale, Lawrence Vernetti, Nina Senutovitch, Rohit Jindal, Manjunath Hegde, Albert Gough, William J McCarty, Ahmet Bakan, Abhinav Bhushan, Tong Y Shun, Inna Golberg, Richard DeBiasio, O Berk Usta, D Lansing Taylor, Martin L Yarmush. In vitro platforms for evaluating liver toxicity. Experimental Biology and Medicine 2014, 239 (9) , 1180-1191. https://doi.org/10.1177/1535370214531872
    98. Graham M. Wynne, Angela J. Russell. Drug Discovery Approaches for Rare Neuromuscular Diseases. 2014, 257-343. https://doi.org/10.1039/9781782624202-00257
    99. Bernard Testa. Metabolism in Drug Development. 2014, 1-26. https://doi.org/10.1002/9783527673261.ch01
    100. Dan Xu, Toshi Nishimura, Sachiko Nishimura, Haili Zhang, Ming Zheng, Ying-Ying Guo, Marylin Masek, Sara A. Michie, Jeffrey Glenn, Gary Peltz, . Fialuridine Induces Acute Liver Failure in Chimeric TK-NOG Mice: A Model for Detecting Hepatic Drug Toxicity Prior to Human Testing. PLoS Medicine 2014, 11 (4) , e1001628. https://doi.org/10.1371/journal.pmed.1001628
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