Toxicogenomics

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Toxicogenomics is a subdiscipline of pharmacology that deals with the collection, interpretation, and storage of information about gene and protein activity within a particular cell or tissue of an organism in response to exposure to toxic substances. Toxicogenomics combines toxicology with genomics or other high-throughput molecular profiling technologies such as transcriptomics, proteomics and metabolomics. [1] [2] Toxicogenomics endeavors to elucidate the molecular mechanisms evolved in the expression of toxicity, and to derive molecular expression patterns (i.e., molecular biomarkers) that predict toxicity or the genetic susceptibility to it. [3]

Contents

Pharmaceutical research

In pharmaceutical research, toxicogenomics is defined as the study of the structure and function of the genome as it responds to adverse xenobiotic exposure. It is the toxicological subdiscipline of pharmacogenomics, which is broadly defined as the study of inter-individual variations in whole-genome or candidate gene single-nucleotide polymorphism maps, haplotype markers, and alterations in gene 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 as chemogenomics to describe essentially the same field of study. [7]

Bioinformatics

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 of bioinformatics and statistics, [8] often including statistical classification approaches. [9]

Drug discovery

In pharmaceutical drug discovery and development, toxicogenomics is used to study possible adverse (i.e. toxic) effects of pharmaceutical drugs in defined model systems in order to draw conclusions on the toxic risk to patients or the environment. Both the United States Environmental Protection Agency (EPA) and the Food 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]

Public projects

Chemical Effects in Biological Systems is a project hosted by the National Institute of Environmental Health Sciences building a knowledge base of toxicology studies including study design, clinical pathology, and histopathology and toxicogenomics data. [11] [12]

InnoMed PredTox assesses the value of combining results from various omics 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 the FDA's "Critical Path Initiative". [13]

ToxCast is a program for Predicting Hazard, Characterizing Toxicity Pathways, and Prioritizing the Toxicity Testing of Environmental Chemicals at the United States Environmental Protection Agency. [15]

Tox21 is a federal collaboration involving the National 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 the 1000 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]

See also

Related Research Articles

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Pharmacology is the science of drugs and medications, including a substance's origin, composition, pharmacokinetics, pharmacodynamics, therapeutic use, and toxicology. More specifically, it is the study of the interactions that occur between a living organism and chemicals that affect normal or abnormal biochemical function. If substances have medicinal properties, they are considered pharmaceuticals.

<span class="mw-page-title-main">Toxicology</span> Study of substances harmful to living organisms

Toxicology is a scientific discipline, overlapping with biology, chemistry, pharmacology, and medicine, that involves the study of the adverse effects of chemical substances on living organisms and the practice of diagnosing and treating exposures to toxins and toxicants. The relationship between dose and its effects on the exposed organism is of high significance in toxicology. Factors that influence chemical toxicity include the dosage, duration of exposure, route of exposure, species, age, sex, and environment. Toxicologists are experts on poisons and poisoning. There is a movement for evidence-based toxicology as part of the larger movement towards evidence-based practices. Toxicology is currently contributing to the field of cancer research, since some toxins can be used as drugs for killing tumor cells. One prime example of this is ribosome-inactivating proteins, tested in the treatment of leukemia.

<span class="mw-page-title-main">Pharmacogenomics</span> Study of the role of the genome in drug response

Pharmacogenomics, often abbreviated "PGx," is the study of the role of the genome in drug response. Its name reflects its combining of pharmacology and genomics. Pharmacogenomics analyzes how the genetic makeup of a patient affects their response to drugs. It deals with the influence of acquired and inherited genetic variation on drug response, by correlating DNA mutations with pharmacokinetic, pharmacodynamic, and/or immunogenic endpoints.

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<span class="mw-page-title-main">KEGG</span> Collection of bioinformatics databases

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The Comparative Toxicogenomics Database (CTD) is a public website and research tool launched in November 2004 that curates scientific data describing relationships between chemicals/drugs, genes/proteins, diseases, taxa, phenotypes, GO annotations, pathways, and interaction modules. The database is maintained by the Department of Biological Sciences at North Carolina State University.

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The Pharmacogenomics Knowledgebase (PharmGKB) is a publicly available, online knowledge base responsible for the aggregation, curation, integration and dissemination of knowledge regarding the impact of human genetic variation on drug response. It is funded by the National Institutes of Health (NIH) National Institute of General Medical Sciences (NIGMS), and is a partner of the NIH Pharmacogenomics Research Network (PGRN). It has been managed at Stanford University since its inception in 2000.

eTOX Toxicology data consortium

eTOX is a temporary consortium established in 2010 to share and use toxicology data. It is a pre-competitive collaboration which main goal is to create and distribute tools to predict drug side-effects based on pre-clinical experiments. Aims are a better in silico predictability of potential adverse events and a decrease of the use of animals in toxicological research. eTOX is funded by the Innovative Medicines Initiative (IMI).

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References

  1. ↑ National Research Council (US) Committee on Communicating Toxicogenomics Information to Nonexperts (2005). Communicating Toxicogenomics Information to Nonexperts: A Workshop Summary. The National Academies Press. doi:10.17226/11179. ISBN   978-0-309-09538-9. PMID   20669449.
  2. ↑ Hamadeh HK, Afshari CA, eds. (2004). Toxicogenomics: Principles and Applications. Hoboken, NJ: Wiley-Liss. ISBN   0-471-43417-5.
    Omenn GS (November 2004). "Book Review: Toxicogenomics: Principles and Applications". Environ. Health Perspect. 112 (16): A962. doi:10.1289/ehp.112-1247673. PMC   1247673 .
  3. ↑ Meier, Matthew J.; Harrill, Joshua; Johnson, Kamin; Thomas, Russell S.; Tong, Weida; Rager, Julia E.; Yauk, Carole L. (2024-09-02). "Progress in toxicogenomics to protect human health". Nature Reviews Genetics: 1–18. doi:10.1038/s41576-024-00767-1. ISSN   1471-0064.
  4. ↑ Lesko LJ, Woodcock J (2004). "Translation of pharmacogenomics and pharmacogenetics: a regulatory perspective". Nature Reviews. Drug Discovery. 3 (9): 763–9. doi:10.1038/nrd1499. PMID   15340386. S2CID   33145913.
  5. ↑ Lesko LJ, Salerno RA, Spear BB, Anderson DC, Anderson T, Brazell C, Collins J, Dorner A, Essayan D, Gomez-Mancilla B, Hackett J, Huang SM, Ide S, Killinger J, Leighton J, Mansfield E, Meyer R, Ryan SG, Schmith V, Shaw P, Sistare F, Watson M, Worobec A (2003). "Pharmacogenetics and pharmacogenomics in drug development and regulatory decision making: report of the first FDA-PWG-PhRMA-DruSafe Workshop". Journal of Clinical Pharmacology. 43 (4): 342–58. doi:10.1177/0091270003252244. PMID   12723455. S2CID   5902873.
  6. ↑ Nuwaysir EF, Bittner M, Trent J, Barrett JC, Afshari CA (1999). "Microarrays and toxicology: the advent of toxicogenomics". Molecular Carcinogenesis. 24 (3): 153–9. doi:10.1002/(SICI)1098-2744(199903)24:3<153::AID-MC1>3.0.CO;2-P. PMID   10204799.
  7. ↑ Fielden MR, Pearson C, Brennan R, Kolaja KL (2005). "Preclinical drug safety analysis by chemogenomic profiling in the liver". American Journal of Pharmacogenomics. 5 (3): 161–71. doi:10.2165/00129785-200505030-00003. PMID   15952870. S2CID   24834075.
  8. ↑ Mattes WB, Pettit SD, Sansone SA, Bushel PR, Waters MD (March 2004). "Database development in toxicogenomics: issues and efforts". Environmental Health Perspectives. 112 (4): 495–505. doi:10.1289/ehp.6697. PMC   1241904 . PMID   15033600. Archived from the original on 2008-07-04.
  9. ↑ 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. doi:10.1016/j.mrfmmm.2007.06.010. PMID   17689568.
  10. ↑ Corvi R, Ahr HJ, Albertini S, Blakey DH, Clerici L, Coecke S, Douglas GR, Gribaldo L, Groten JP, Haase B, Hamernik K, Hartung T, Inoue T, Indans I, Maurici D, Orphanides G, Rembges D, Sansone SA, Snape JR, Toda E, Tong W, van Delft JH, Weis B, Schechtman LM (March 2006). "Meeting report: Validation of toxicogenomics-based test systems: ECVAM-ICCVAM/NICEATM considerations for regulatory use". Environmental Health Perspectives. 114 (3): 420–9. doi:10.1289/ehp.8247. PMC   1392237 . PMID   16507466. Archived from the original on 2008-10-17.
  11. ↑ Waters MD, Fostel JM (2004). "Toxicogenomics and systems toxicology: aims and prospects". Nature Reviews Genetics. 5 (12): 938–948. doi:10.1038/nrg1493. PMID   15573125. S2CID   1368324.
  12. ↑ 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. PMID   17916055. S2CID   27489795.
  13. 1 2 Mattes WB (2008). "Public Consortium Efforts in Toxicogenomics". In Mendrick DL, Mattes WB (eds.). Essential Concepts in Toxicogenomics. Methods in Molecular Biology. Vol. 460. pp. 221–238. doi:10.1007/978-1-60327-048-9_11. ISBN   978-1-58829-638-2. PMID   18449490.
  14. ↑ Igarashi Y, Nakatsu N, Yamashita T, Ono A, Ohno Y, Urushidani T, Yamada H (January 2015). "Open TG-GATEs: a large-scale toxicogenomics database". Nucleic Acids Research. 43 (Database issue): D921–7. doi:10.1093/nar/gku955. PMC   4384023 . PMID   25313160.
  15. ↑ Dix DJ, Houck KA, Martin MT, Richard AM, Setzer RW, Kavlock RJ (January 2007). "The ToxCast program for prioritizing toxicity testing of environmental chemicals". Toxicological Sciences. 95 (1): 5–12. doi: 10.1093/toxsci/kfl103 . PMID   16963515.
  16. ↑ "Toxicology in the 21st century project". www.ncats.nih.gov.
  17. ↑ Abdo N, Xia M, Brown CC, Kosyk O, Huang R, Sakamuru S, Zhou YH, Jack JR, Gallins P, Xia K, Li Y, Chiu WA, Motsinger-Reif AA, Austin CP, Tice RR, Rusyn I, Wright FA (May 2015). "Population-based in vitro hazard and concentration-response assessment of chemicals: the 1000 genomes high-throughput screening study". Environmental Health Perspectives. 123 (5): 458–66. doi:10.1289/ehp.1408775. PMC   4421772 . PMID   25622337.
  18. ↑ "NIEHS-NCATS-UNC-DREAM Toxicogenetics Challenge". Sage Bionetworks.
  19. ↑ "DeepTox: Deep Learning for Toxicity Prediction". Institute of Bioinformatics, Johannes Kepler University Linz.
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