Development of a toxicogenomics in vitro assay for the efficient characterization of compounds

Pharmacogenomics
Yi YangJeffrey F Waring

Abstract

In vitro toxicogenomics represents a useful approach for evaluating the toxic properties of new drug candidates early in the drug discovery process using minimal amounts of compounds. The aim of this study was to develop in vitro-based gene expression assays for two prototypical toxicological classes: aryl hydrocarbon receptor (AhR) agonists and peroxisome proliferator activated receptor alpha (PPAR alpha) agonists. Primary rat hepatocytes were exposed to a number of class-specific compounds, including 3-methylcholanthrene, aroclor, and beta-napthoflavone as AhR agonists, bezafibrate, clofibrate, and Wy-14643 as peroxisome proliferators, and chlorpheniramine, penicillin and spectinomycin as negative controls. Global gene expression profiles were generated with microarrays for each class of compounds. Using linear discriminant analysis coupled with permutation-based t-test, gene signatures were established to classify compounds according to a discriminant score. The final gene signatures consist of eight genes for AhR agonism and 11 genes for PPAR alpha agonism, and were further validated using additional compounds. The assay was initially developed using a microarray platform. The authors then evaluated whether it could be tran...Continue Reading

References

May 3, 1996·The Journal of Biological Chemistry·C G BroustasA K Hajra
Feb 12, 1998·The Journal of Biological Chemistry·M BacklundM Ingelman-Sundberg
Oct 6, 2000·Drug Discovery Today·D E Johnson, G H Wolfgang
Dec 2, 2000·Toxicological Sciences : an Official Journal of the Society of Toxicology·M E BurczynskiM D Johnson
Aug 18, 2001·Toxicology and Applied Pharmacology·J F WaringR G Ulrich
Jan 24, 2003·Annual Review of Pharmacology and Toxicology·Michael S Denison, Scott R Nagy
Feb 13, 2003·Nucleic Acids Research·Rafael A IrizarryTerence P Speed
Jun 14, 2003·Toxicological Sciences : an Official Journal of the Society of Toxicology·Christopher H Hurst, David J Waxman
Jul 2, 2003·Toxicological Sciences : an Official Journal of the Society of Toxicology·Bart A JessenGregory J Stevens
Aug 3, 2004·Nature Reviews. Drug Discovery·Ismail Kola, John Landis
Oct 23, 2004·Biochemical Pharmacology·Michael McMillianMark D Johnson
Nov 4, 2004·Chemico-biological Interactions·Yi YangJeffrey F Waring
Jan 26, 2005·Toxicology and Applied Pharmacology·Paul R HanlonColin R Jefcoate
Mar 10, 2005·Neurobiology of Disease·Deborah HollingsheadKároly Mirnics

❮ Previous
Next ❯

Citations

Jun 6, 2009·Nature Reviews. Neurology·Chiara Zuccato, Elena Cattaneo
Dec 11, 2007·Toxicological Sciences : an Official Journal of the Society of Toxicology·Robert J KavlockEric Weber
Jan 8, 2008·Toxicological Sciences : an Official Journal of the Society of Toxicology·Jay B SilkworthThomas R Sutter
Jul 14, 2012·Toxicological Sciences : an Official Journal of the Society of Toxicology·Minjun ChenWeida Tong
Sep 11, 2008·Pharmacogenomics·Chris Cotsapas
Oct 22, 2009·Pharmacogenomics·Daniel S JohnstonSalvatore Alesci
Jan 1, 2014·Advanced Drug Delivery Reviews·Adrian Roth, Thomas Singer
Nov 21, 2015·Chemical Research in Toxicology·Eric Blomme, Yvonne Will
Jan 22, 2008·Toxicology·Donna L Mendrick
May 22, 2007·Toxicology in Vitro : an International Journal Published in Association with BIBRA·F BoessL Suter
Jul 13, 2013·Critical Reviews in Toxicology·Michael DoursonPenelope A Fenner-Crisp
Sep 12, 2006·Toxicological Sciences : an Official Journal of the Society of Toxicology·David J DixRobert J Kavlock
Jul 7, 2009·The Journal of Veterinary Medical Science·Hye-Jung YeomSeung Yong Hwang
Aug 11, 2020·Expert Opinion on Drug Metabolism & Toxicology·Eita SasakiTakuo Mizukami

❮ Previous
Next ❯

Methods Mentioned

BETA
Assay
PCR

Software Mentioned

Affymetrix
Rosetta Resolver
TLDA
SAS

Related Concepts

Trending Feeds

COVID-19

Coronaviruses encompass a large family of viruses that cause the common cold as well as more serious diseases, such as the ongoing outbreak of coronavirus disease 2019 (COVID-19; formally known as 2019-nCoV). Coronaviruses can spread from animals to humans; symptoms include fever, cough, shortness of breath, and breathing difficulties; in more severe cases, infection can lead to death. This feed covers recent research on COVID-19.

Blastomycosis

Blastomycosis fungal infections spread through inhaling Blastomyces dermatitidis spores. Discover the latest research on blastomycosis fungal infections here.

Nuclear Pore Complex in ALS/FTD

Alterations in nucleocytoplasmic transport, controlled by the nuclear pore complex, may be involved in the pathomechanism underlying multiple neurodegenerative diseases including Amyotrophic Lateral Sclerosis and Frontotemporal Dementia. Here is the latest research on the nuclear pore complex in ALS and FTD.

Applications of Molecular Barcoding

The concept of molecular barcoding is that each original DNA or RNA molecule is attached to a unique sequence barcode. Sequence reads having different barcodes represent different original molecules, while sequence reads having the same barcode are results of PCR duplication from one original molecule. Discover the latest research on molecular barcoding here.

Chronic Fatigue Syndrome

Chronic fatigue syndrome is a disease characterized by unexplained disabling fatigue; the pathology of which is incompletely understood. Discover the latest research on chronic fatigue syndrome here.

Evolution of Pluripotency

Pluripotency refers to the ability of a cell to develop into three primary germ cell layers of the embryo. This feed focuses on the mechanisms that underlie the evolution of pluripotency. Here is the latest research.

Position Effect Variegation

Position Effect Variagation occurs when a gene is inactivated due to its positioning near heterochromatic regions within a chromosome. Discover the latest research on Position Effect Variagation here.

STING Receptor Agonists

Stimulator of IFN genes (STING) are a group of transmembrane proteins that are involved in the induction of type I interferon that is important in the innate immune response. The stimulation of STING has been an active area of research in the treatment of cancer and infectious diseases. Here is the latest research on STING receptor agonists.

Microbicide

Microbicides are products that can be applied to vaginal or rectal mucosal surfaces with the goal of preventing, or at least significantly reducing, the transmission of sexually transmitted infections. Here is the latest research on microbicides.