Applications in Toxicology & Hepatobiology

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App Notes & Tech Briefs

Screening for Mitochondrial Biogenesis and Toxicity

A sensitive and robust cell-based screening assay.

Mitochondrial damage compromises ATP production and consequentially cellular viability. Given the central role that mitochondria play in regulating cellular function, drugs that undermine mitochondrial function frequently elicit toxic effects...
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Publications

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Mitochondrial Dysfunction Assessed Quantitatively in Real Time by Measuring the Extracellular Flux of Oxygen and Protons
Ferrick D, Wu M, Swift A L and Neilson A
Drug-Induced Mitochondrial Dysfunction; 2008 Jan 22. :Ch 14.
In vitro assessment of mitochondrial dysfunction and cytotoxicity of nefazodone, trazodone, and buspirone
Dykens J A, Jamieson J D, Marroquin L D, Nadanaciva S, Xu J J, Dunn M C, Smith A R and Will Y
Toxicol Sci; 2008 Jun 1. 103 (2):335-345.
Biguanide-induced mitochondrial dysfunction yields increased lactate production and cytotoxicity of aerobically-poised HepG2 cells and human hepatocytes in vitro
Dykens J A, Jamieson J, Marroquin L, Nadanaciva S, Billis P A and Will Y
Toxicol Appl Pharmacol; 2008 Dec 1. 233 (2):203-210.
The role of CYP3A4 in amiodarone-associated toxicity on HepG2 cells
Zahno A, Brecht K, Morand R, Maseneni S, Torok M, Lindinger P W and Krahenbuhl S
Biochem Pharmacol; 2011 Feb 1. 81 (3):432-441.
Metabolic profiles show specific mitochondrial toxicities in vitro in myotube cells
Xu Q, Vu H, Liu L, Wang T C and Schaefer W H
J Biomol NMR; 2011 Apr 1. 49 (4-Mar):207-219.
Mitochondrial development of the in vitro hepatic organogenesis model with simultaneous cardiac mesoderm differentiation from murine induced pluripotent stem cells
Tamai M, Yamashita A and Tagawa Y I
J Biosci Bioeng; 2011 Nov 1. 112 (5):495-500.
Caveolin-1 orchestrates the balance between glucose and lipid-dependent energy metabolism: implications for liver regeneration
Fernandez-Rojo M A, Restall C, Ferguson C, Martel N, Martin S, Bosch M, Kassan A, Leong G M, Martin S D, McGee S L, Muscat G E, Anderson R L, Enrich C, Pol A and Parton R G
Hepatology. 2011 Nov 22; [Epub ahead of print].
Susceptibility to simvastatin-induced toxicity is partly determined by mitochondrial respiration and phosphorylation state of Akt
Mullen P J, Zahno A, Lindinger P, Maseneni S, Felser A, Krahenbuhl S and Brecht K
Biochim Biophys Acta; 2011 Dec 1. 1813 (12):2079-87.
Nitric oxide and hypoxia exacerbate alcohol-induced mitochondrial dysfunction in hepatocytes
Zelickson B R, Benavides G A, Johnson M S, Chacko B K, Venkatraman A, Landar A, Betancourt A M, Bailey S M and Darley-Usmar V M
Biochim Biophys Acta; 2011 Dec 1. 1807 (12):1573-82.
Molecular Analysis of Mitochondrial Compromise in Rodent Cardiomyocytes Exposed Long Term to Nucleoside Reverse Transcriptase Inhibitors (NRTIs)
Liu Y, Nguyen P, Baris T Z and Poirier M C
Cardiovasc Toxicol. 2011 Dec 15; [Epub ahead of print].
Ethanol Suppresses Ureagenesis in Rat Hepatocytes: Role of Acetaldehyde
Holmuhamedov E L, Czerny C, Beeson C C and Lemasters J J
J Biol Chem. 2012 Jan 6; [Epub ahead of print].
Hemin causes mitochondrial dysfunction in endothelial cells through promoting lipid peroxidation: The protective role of autophagy
Higdon A N, Benavides G A, Chacko B K, Ouyang X, Johnson M S, Landar A, Zhang J and Darley-Usmar V M
Am J Physiol Heart Circ Physiol. 2012 Jan 13; [Epub ahead of print].
Gene-dose influences cellular and calcium channel dysregulation in heterozygous and homozygous T4826I-RYR1 malignant hyperthermia susceptible muscle
Barrientos G C, Feng W, Truong K, Matthaei K I, Yang T, Allen P D, Lopez J R and Pessah I N
J Biol Chem; 2012 Jan 20. 287 (4):2863-76.
The impact of assay technology as applied to safety assessment in reducing compound attrition in drug discovery
Thomas C E and Will Y
Expert Opinion on Drug Discovery; 2012 Feb 1. 7 (2):109-122.

Technical Posters

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Chronic ethanol consumption increases the sensitivity of hepatocyte mitochondria to NO-dependent bioenergetic dysfunction.
Gloria A. Benavides, Blake R. Zelickson, Michelle S. Johnson, Balu K. Chacko, Aimee Landar, Victor Darley-Usmar
Society for Free Radical Biology and Medicine (SFRBM) 2011
November 16-20, 2011
Atlanta, GA
Assessment of mitochondrial dysfunction and cytotoxicity of bisphenol A in isolated hepatocytes
Angela M. Betancourt and Shannon M. Bailey
Society for Free Radical Biology and Medicine (SFRBM) 2011
November 16-20, 2011
Atlanta, GA
Abrupt Alcohol Withdrawal Suppresses Mitochondrial Repiration in an Estrogen Preventable Manner
Xiaohua Ju, Daniel Metzger, Yi Wen, Shaohua Yang, James W. Simpkins and Marianna Jung
Neuroscience 2010
November 13-17, 2010
San Diego, CA
Simvastatin: The Enemy Within?
PJ Mullen, A Zahno, S Maseneni, S Krahensbuhl, P Lindinger
European Muscle Conference, XXXIX
September 14, 2010
Padua, IT
In vitro Detection of Pharmaceutical Compounds that Disturb Mitochondrial Functions
Irene Edebert, Ingalill Rafter, Ian Cotgreave
46th Congress of the European Societies of Toxicology
September 13-16, 2009
Dresden, Germany

Webinars

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Using Reserve Capacity to Screen for Mitochondrial Toxicities and Biogenesis
Craig C. Beeson, PhD, Medical University of South Carolina
March 23, 2011
Primary Renal Proximal Tubules as a Platform for Mitochondrial Biogenesis and Toxicity Assays
Craig Beeson, PhD , Medical University of South Carolina
June 24, 2009
Fluorescent Reporters of Mitochondrial Function in the Life and Death of Cells
John J. LeMasters, MD, PhD, Medical University of South Carolina
February 18, 2009
Achieving Higher Throughput and Greater Content When Measuring Mitochondrial Function
David Ferrick, PhD, CSO, Seahorse Bioscience
January 22, 2009
Mitochondrial Toxicity: Designing Novel Screening Methods to Reduce NCE Attrition
Yvonne Will, PhD, Cell Based Assays, Pfizer
September 24, 2008
Tutorial: Measuring Bioenergetics in a Variety of Cell Types
David Ferrick, PhD, CSO, Seahorse Bioscience
July 17, 2008

In vitro toxicity testing is the scientific analysis of the effects of toxic chemical substances on cultured cells. In vitro testing methods are used to confirm the lack of certain toxic properties in the early stages of the development of potentially useful new substances such as therapeutic drugs. The XF Analyzer allows the measurement of cellular metabolism in real time, in a microplate.

The XF Analyzer generates data that can provide new understanding in relation to in vitro toxicity and mitochondrial dysfunction, by allowing the measurement of cellular metabolism in real-time, in a microplate. By measuring the oxygen consumption rate (OCR) - a measure of mitochondrial respiration; as well as the extracellular acidification rate (ECAR) - a measure of glycolysis, you will be provided with the most physiologically relevant in vitro measurement for your bioenergetic studies.