Toxicogenomics is a subdiscipline ofpharmacology that deals with the collection, interpretation, and storage of information aboutgene andprotein activity within a particularcell ortissue of anorganism in response to exposure totoxic substances. Toxicogenomics combinestoxicology withgenomics or other high-throughput molecular profiling technologies such astranscriptomics,proteomics andmetabolomics.[1][2] Toxicogenomics endeavors to elucidate the molecular mechanisms evolved in the expression of toxicity, and to derive molecular expression patterns (i.e., molecularbiomarkers) that predict toxicity or the genetic susceptibility to it.[3]
In pharmaceutical research, toxicogenomics is defined as the study of the structure and function of thegenome as it responds to adverse xenobiotic exposure. It is the toxicological subdiscipline ofpharmacogenomics, which is broadly defined as the study of inter-individual variations in whole-genome or candidate genesingle-nucleotide polymorphism maps,haplotype markers, and alterations ingene expression that might correlate with drug responses.[4][5] Though the term toxicogenomics first appeared in the literature in 1999,[6] it was by that time already in common use within the pharmaceutical industry as its origin was driven by marketing strategies from vendor companies. The term is still not universally accepted, and others have offered alternative terms such aschemogenomics to describe essentially the same field of study.[7]
The nature and complexity of the data (in volume and variability) demands highly developed processes of automated handling and storage. The analysis usually involves a wide array ofbioinformatics andstatistics,[8] often includingstatistical classification approaches.[9]
In pharmaceuticaldrug discovery anddevelopment, toxicogenomics is used to study possibleadverse (i.e.toxic) effects of pharmaceuticaldrugs in definedmodel systems in order to draw conclusions on the toxic risk to patients or the environment. Both theUnited States Environmental Protection Agency (EPA) and theFood and Drug Administration (FDA) currently preclude basing regulatory decision-making on genomics data alone. However, they do encourage the voluntary submission of well-documented, quality genomics data. Both agencies are considering the use of submitted data on a case-by-case basis for assessment purposes (e.g., to help elucidate mechanism of action or contribute to a weight-of-evidence approach) or for populating relevant comparative databases by encouraging parallel submissions of genomics data and traditional toxicological test results.[10]
InnoMed PredTox assesses the value of combining results from variousomics technologies together with the results from more conventional toxicology methods in more informed decision-making in preclinical safety evaluation.[13]
Open TG-GATEs (Toxicogenomics Project-Genomics Assisted Toxicity Evaluation System) is a Japanese public-private effort which has published gene expression and pathology information for more than 170 compounds (mostly drugs).[14]
The Predictive Safety Testing Consortium aims to identify and clinically qualify safety biomarkers for regulatory use as part of theFDA's "Critical Path Initiative".[13]
ToxCast is a program for Predicting Hazard, Characterizing Toxicity Pathways, and Prioritizing the Toxicity Testing of Environmental Chemicals at theUnited States Environmental Protection Agency.[15]
Tox21 is a federal collaboration involving theNational Institutes of Health (NIH), Environmental Protection Agency (EPA), and Food and Drug Administration (FDA), is aimed at developing better toxicity assessment methods.[16] Within this project the toxic effects of chemical compounds on cell lines derived from the1000 Genomes Project individuals were assessed and associations with genetic markers were determined.[17] Parts of this data were used in the NIEHS-NCATS-UNC DREAM Toxicogenetics Challenge in order to determine methods for cytotoxicity predictions for individuals.[18][19]
^Ellinger-Ziegelbauer H, Gmuender H, Bandenburg A, Ahr HJ (January 2008). "Prediction of a carcinogenic potential of rat hepatocarcinogens using toxicogenomics analysis of short-term in vivo studies".Mutation Research.637 (1–2):23–39.Bibcode:2008MRFMM.637...23E.doi:10.1016/j.mrfmmm.2007.06.010.PMID17689568.
^Waters MD, Fostel JM (2004). "Toxicogenomics and systems toxicology: aims and prospects".Nature Reviews Genetics.5 (12):938–948.doi:10.1038/nrg1493.PMID15573125.S2CID1368324.
^Collins BC, Clarke A, Kitteringham NR, Gallagher WM, Pennington SR (October 2007). "Use of proteomics for the discovery of early markers of drug toxicity".Expert Opinion on Drug Metabolism & Toxicology.3 (5):689–704.doi:10.1517/17425255.3.5.689.PMID17916055.S2CID27489795.
