Mitochondrial Toxicity Assessment

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 Books Edited: 

Yvonne Will and James Dykens, (Editors) 2018. Mitochondrial Dysfunction Caused by Drugs and Environmental Toxicants. Volume I and II. John Wiley& Sons Inc, New York, NY


J. A. Dykens and Y. Will, (Editors) 2008. Drug induced mitochondrial Toxicities. John Wiley& Sons Inc, New York, NY.


Review Articles:

James Hynes and Yvonne Will. The Evolution of Mitochondrial Toxicity Assessment in Industry. Mitochondrial Biology and Experimental Therapeutics, 2018 Editor: Paulo Oliveira. Springer Protocols, Humana Press, New York, NY.


Will Y, Dykens J. Mitochondrial toxicity assessment in industry--a decade of technology development and insight. Expert Opin Drug Metab Toxicol. 2014 Aug; 10(8):1061-7.

 

Nadanaciva S, Will Y. New insights in drug-induced mitochondrial toxicity. Curr Pharm Des. 2011; 17(20):2100-12.

 

Nadanaciva, S. and Will, Y.  Investigating Mitochondrial Dysfunction to Increase Drug Safety in the Pharmaceutical Industry” Current Drug Targets 2012


James A. Dykens and Yvonne Will, Drug-Induced Mitochondrial Dysfunction: An Emerging Model of Idiosyncratic Drug Toxicity American Drug Discovery June 2009


Sashi Nadanaciva and Yvonne Will. The Role of Mitochondrial Dysfunction and Drug Safety. Drug Information - Key Opinions Healthcare and Science, October 2009


James A. Dykens and Yvonne Will. Biomarkers of In Vitro Drug-Associated Mitochondrial Dysfunction. In: “Biomarkers of toxicity: A New Era in Medicine”. Vishal S. Vaidya and Joseph V. Bonventre Editors. John Wiley and Sons, 2009.


Dykens JA, Will Y. The significance of mitochondrial toxicity testing in drug development. Drug Discov Today. 2007 Sep; 12(17-18):777-85


Dykens JA, Marroquin LD, Will Y. Strategies to reduce late-stage drug attrition due to mitochondrial toxicity.Expert Rev Mol Diagn. 2007 Mar; 7(2):161-75. 


Nadanaciva, S and Will, Y. Predicting Drug-Induced Mitochondrial Dysfunction. Book chapter submitted to New Horizons in Toxicity Prediction: A Comprehensive Overview of the Current Status and Application of Predictive Toxicology (ed. A. Wilson); Royal Society of Chemistry, UK. 2007


Papkovsky DB, Hynes J, Will Y. Respirometric Screening Technology for ADME-Tox studies. Expert Opin Drug Metab Toxicol. 2006 Apr; 2(2):313-23.


Peer Reviewed Publications:

Rana, P., Aleo, M, Gosink, M and Will, Y. Evaluation of In Vitro Mitochondrial Toxicity Assays and Physicochemical Properties for Prediction of Organ Toxicity Using 228 Pharmaceutical Drugs. Chem. Res. Toxicol., 2019, 32 (1), pp 156–167


Hynes J, Swiss RL, Will Y. High-Throughput Analysis of Mitochondrial Oxygen Consumption. Methods Mol Biol. 2018; 1782:71-87.

 

Hynes J, Carey C, Will Y. Fluorescence-Based Microplate Assays for In Vitro Assessment of Mitochondrial Toxicity, Metabolic Perturbation, and Cellular Oxygenation. Curr Protoc Toxicol. 2016 Nov 1; 70:2.16.1-2.16.30. 


Marroquin L, Swiss R, Will Y. Identifying Compounds that Induce Opening of the Mitochondrial Permeability Transition Pore in Isolated Rat Liver Mitochondria. Curr Protoc Toxicol. 2014 May 27; 60:25.4.1-25.4.17

Rogers GW, Nadanaciva S, Swiss R, Divakaruni AS, Will Y. Assessment of Fatty Acid Beta oxidation in cells and isolated mitochondria. Curr Protoc Toxicol. 2014 May 27; 60:25.3.1-25.3.19. 


James Hynes, Sashi Nadanaciva, Rachel Swiss, Conn Carey, Sinead Kirwan, Yvonne Will. A high-throughput dual parameter assay for assessing drug-induced mitochondrial dysfunction provides additional predictivity over two established mitochondrial toxicity assays. Toxicol In Vitro. 2013 Mar; 27(2):560-9.


Naven RT, Swiss R, McLeod JK, Will Y, Greene N. The Development of a Structure-Activity Relationships for Mitochondrial Dysfunction: Uncoupling of Oxidative Phosphorylation. Toxicol Sci. 2013 Jan; 131(1):271-8.


Rana P., Nadanaciva, S., and Will, Y. Mitochondrial Membrane Potential Measurement of H9c2 cells Grown in High-Glucose and Galactose Containing Media Does Not Provide Additional Predictivity Towards Mitochondrial Assessment; Toxicology in Vitro, 2011 Mar;25(2):580-7


Nadanaciva, S., Dillman, K., Gebhard, D.F., Shrikhande, A., and Will, Y. High-content screening for compounds that affect mtDNA-encoded protein levels in eukaryotic cells J Biomol Screen. 2010; 15(8):937-48.


Hynes J, O'Riordan TC, Zhdanov AV, Uray G, Will Y, Papkovsky DB. In vitro analysis of cell metabolism using a long-decay pH-sensitive lanthanide probe and extracellular acidification assay. Anal Biochem. 2009 Jul 1; 390(1):


Nadanaciva S, Willis JH, Barker ML, Gharaibeh D, Capaldi RA, Marusich MF, Will Y. Lateral-flow immunoassay for detecting drug-induced inhibition of mitochondrial DNA replication and mtDNA-encoded protein synthesis. J Immunol Methods. 2009 Mar 31; 343(1):1-12.


Ogurtsov, V.I., Hynes J., Will, Y., and Papkovsky, D.B., 2008. Data analysis algorithm for high throughput enzymatic oxygen consumption assays based on quenched-fluorescence detection. Sensor Actuat B-Chem: 129, (2): 581-590.


Dykens JA, Jamieson J, Marroquin L, Nadanaciva S, Billis PA, Will Y. Biguanide-induced mitochondrial dysfunction yields increased lactate production and cytotoxicity of aerobically-poised HepG2 cells and human hepatocytes in vitro. Toxicol Appl Pharmacol. 2008 Dec 1; 233(2):203-10.

 

Yvonne Will, Dykens, JA, Marroquin, LM, Hirakawa, B., Jamieson, J and Jessen, B. Effect of the Multi-targeted Tyrosine Kinase Inhibitors Imatinib, Dasatinib, Sunitinib and Sorafenib on Mitochondrial Function in Isolated Rat Heart Mitochondria and H9c2 cells. Toxicol Sci. 2008 Nov; 106(1):153-61

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Dykens JA, Jamieson JD, Marroquin LD, Nadanaciva S, Xu JJ, Dunn MC, Smith AR, Will Y. In Vitro Assessment of Mitochondrial Dysfunction and Cytotoxicity of Nefazodone, Trazodone and Buspirone. Toxicol Sci. 2008 Jun; 103(2):335-45


V.I. Ogurtsov, J. Hynes, Y. Will, D.B. Papkovsky, Data analysis algorithm for high throughput enzymatic oxygen consumption assays based on quenched-fluorescence detection, Sensors and Actuators B: Chemical (2007), doi:10.1016/j.snb.2007.09.004


Nadanaciva S, Dykens JA, Bernal A, Capaldi RA, Will Y. Mitochondrial impairment by PPAR agonists and statins identified via immunocaptured OXPHOS complex activities and respiration.Toxicol Appl Pharmacol. 2007 Sep 15; 223(3):277-87. 


Will Y, Hynes J, Ogurtsov VI, Papkovsky DB. Analysis of mitochondrial function using phosphorescent oxygen-sensitive probes. Nat Protoc. 2006; 1(6):2563-72. 


Marroquin LD, Hynes J, Dykens JA, Jamieson JD, Will Y. Circumventing the Crabtree effect: replacing media glucose with galactose increases susceptibility of HepG2 cells to mitochondrial toxicants.Toxicol Sci. 2007 Jun;97(2):539-47. 


Nadanaciva S, Bernal A, Aggeler R, Capaldi R, Will Y. Target identification of drug induced mitochondrial toxicity using immunocapture based OXPHOS activity assays. Toxicol in Vitro. 2007 Aug; 21(5):902-11. 


Hynes J, Marroquin LD, Ogurtsov VI, Christiansen KN, Stevens GJ, Papkovsky DB, Will Y. Investigation of drug-induced mitochondrial toxicity using fluorescence-based oxygen-sensitive probes. Toxicol Sci. 2006 Jul; 92(1):186-200.

Predictive Safety Assessment

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Books Edited:

Minjun Chen and Yvonne Will (Editors) 2018. Drug Induced Liver Toxicity, Spring.er Protocols, Humana Press, New York, NY.


Yvonne Will, Erik McDuffy, Andrew Olaharsky and Brandon Jeffy, (Editors) 2016. Drug Discovery Toxicology - from in silico models to translational biomarkers. John Wiley& Sons Inc, New York, NY.


Review Articles:

Blomme EA, Will Y. Toxicology Strategies for Drug Discovery: Present and Future. Chem Res Toxicol. 2016 Apr 18; 29(4):473-504.


Franck A. Atienzar, Eric A. Blomme, Minjun Chen, Philip Hewit, J. Gerry Kenna, Gilles Labbe, Frederic Moulin, Francois Pognan, Adrian B. Roth, Laura Suter-Dick, Okechukwu Ukairo, Richard Weaver, Yvonne Will, Donna Dambach- Key challenges and opportunities associated with the use of in vitro models to detect human DILI: integrated risk assessment and mitigation plans. Biomed Res Int. 2016; 2016: 9737920.


Will Y, Schroeter T. Deployment of in silico and in vitro safety assays in early-stage drug discovery. Future Med Chem. 2012 Jun; 4(10):1211-3. 


Thomas CE, Will Y. The impact of assay technology as applied to safety assessment in reducing compound attrition in drug discovery. Expert Opin Drug Discov. 2012 Feb; 7(2):109-22.


Pereira CV, Nadanaciva S, Oliveira PJ, Will Y. The contribution of oxidative stress to drug-induced organ toxicity and its detection in vitro and in vivo. Expert Opin Drug Metab Toxicol. 2012 Feb; 8(2):219-37


Xu, X, Kalgutar, A., James Dykens and Yvonne Will: Discovery Toxicology Screening: Predictive, In Vitro Cytotoxicity. In: Hit and Lead Profiling. Identification and Optimization of Drug-like Molecules. Methods and Principles in Medicinal Chemistry (Volume 43). Edited by Mannhold, Raimund / Kubinyi, Hugo / Folkers, Gerd John Wiley and Sons, 2009


Peer Reviewed Publications:

Lorna Ewart; Donna Dambach; Yvonne Dragan; David Duignan; Jeetu Eswaraka; Jingping Gan; Peggy Guzzie-Peck; Monicah Otieno; Claire Jeong; Doug Keller; Sonia M. De Morais; Jonathan Phillips; Will Proctor; Rahda Sura; Terry Van Vleet; David Watson; Yvonne Will; Kristin Fabre; Ananthsrinivas Chakilam; Brian Berridge- Navigating Tissue Chips from Development to Dissemination: A Pharmaceutical Industry Perspective. Experimental Biology and Medicine 2017, 242(16):1559-1572


Butler LD, Guzzie-Peck P, Hartke J, Bogdanffy MS, Will Y, Diaz D, Mortimer-Cassen E, Derzi M, Greene N, DeGeorge JJ. Current nonclinical testing paradigms in support of safe clinical trials: An IQ Consortium DruSafe perspective. Regul Toxicol Pharmacol. 2017 Jul 31; 87 Suppl 3:S1-S15. 


Payal Rana, Yvonne Will, Sashi Nadanaciva, Lyn H. Jones, Development of a cell viability assay to assess drug metabolite structure–toxicity relationships. Bioorg Med Chem Lett. 2016 Aug 15; 26(16):4003-6


Humphreys WG, Will Y, Guengerich FP. Toxicology Strategies for Drug Discovery - Present and Future: Introduction. Chem Res Toxicol. 2016 Apr 18; 29(4):437.


Shah F, Leung L, Barton HA, Will Y, Rodrigues AD, Greene N, Aleo MD. Setting Clinical Exposure Levels of Concern for Drug-Induced Liver Injury (DILI) Using Mechanistic in vitro Assays. Toxicol Sci. 2015 Oct; 147(2):500-14. 


Yang Y, Nadanaciva S, Will Y, Woodhead JL, Howell BA, Watkins PB, Siler SQ. MITOsym®: A Mechanistic, Mathematical Model of Hepatocellular Respiration and Bioenergetics. Pharm Res. 2015 Jun; 32(6).


Aleo MD, Luo Y, Swiss R, Bonin PD, Potter DM, Will Y. Human drug-induced liver injury severity is highly associated to dual inhibition of liver mitochondrial function and bile salt export pump. Hepatology. 2014 May 6


Billis P, Will Y, Nadanaciva S. High-Content Imaging Assays for Identifying Compounds that Generate Superoxide and Impair Mitochondrial Membrane Potential in Adherent Eukaryotic Cells. Curr Protoc Toxicol. 2014 Feb 19; 59:25.1.1-25.


Wager TT, Kormos BL, Brady JT, Will Y, Aleo MD, Stedman DB, Kuhn M, Chandrasekaran RY. Improving the odds of success in drug discovery: choosing the best compounds for in vivo toxicology studies. J Med Chem. 2013 Dec 12; 56(23):9771-9. 


Laifenfeld D, Qiu L, Swiss R, Park J, Macoritto M, Will Y, Younis HS, Lawton M. Utilization of causal reasoning of hepatic gene expression in rats to identify molecular pathways of idiosyncratic drug-induced liver injury. Toxicol Sci. 2014 Jan; 137(1):234-48. 


Nadanaciva S, Aleo MD, Strock CJ, Stedman DB, Wang H, Will Y. Toxicity assessments of nonsteroidal anti-inflammatory drugs in isolated mitochondria, rat hepatocytes, and zebrafish show good concordance across chemical classes. Toxicol Appl Pharmacol. 2013 Oct 15; 272(2):272-80. 


Salman R. Khetani, Chitra Kanchagar, Stacy Krzyzewski, Amanda Moore, Julianne Shi, Simon Aoyama, Michael Aleo, Yvonne Will. Micropatterned Co-cultures Increase the Ability to Detect Compounds that Cause Drug induced Liver Injury in Humans over Sandwich Cultures. Toxicol Sci. 2013 Mar; 132(1):107-17.


Naven RT, Swiss R, McLeod JK, Will Y, Greene N. The Development of a Structure-Activity Relationships for Mitochondrial Dysfunction: Uncoupling of Oxidative Phosphorylation. Toxicol Sci. 2013 Jan; 131(1):271-8.


Rana P, Anson B, Engle S, Will Y. Characterization of Human Induced Pluripotent Stem Cell Derived Cardiomyocytes: Bioenergetics and Utilization in Safety Screening. Toxicol Sci. 2012 Nov; 130(1):117-31


Lu S, Jessen B, Strock C, Will Y. The contribution of physicochemical properties to multiple in vitro cytotoxicity endpoints. Toxicol in Vitro. 2012 Jun; 26(4):613-20. 


Lin Z, Will Y. Evaluation of drugs with specific organ toxicities in organ-specific cell lines. Toxicol Sci. 2012 Mar; 126(1):114-27. 


Nadanaciva, S., Lu, S., Gebhard, D.F., Jessen, B.A., Pennie, W.D., and Will, Y. A High Content Screening Assay for Identifying Lysosomotropic Compounds; Toxicology in vitro. 2011 Apr; 25(3):715-23


Travis T. Wager, Ramalakshmi Y. Chandrasekaran, Xinjun Hou,Matthew D. Troutman, Patrick R. Verhoest, Anabella Villalobos, Yvonne Will. Defining Desirable Central Nervous System Drug Space through the Alignment of Molecular Properties, in Vitro ADME, and Safety Attributes. ACS Chem Neurosci. 2010 Jun 16; 1(6):420-34.


Greene N, Aleo MD, Louise-May S, Price DA, Will Y. Using an in vitro cytotoxicity assay to aid in compound selection for in vivo safety studies. Bioorg Med Chem Lett. 2010 Sep 1; 20(17):5308-12.

A project in BioPharma to validate chromatography resin lifetime cycled a seven column purification train's resins >150 cycles to study the ability for each resin to achieve viral clearance for the chromatographic steps.