Review
Gene to Screen
Zebrafish: a predictive model for assessing drug-induced toxicity

https://doi.org/10.1016/j.drudis.2008.03.002Get rights and content

The zebrafish model organism is increasingly used for assessing drug toxicity and safety and numerous studies confirm that mammalian and zebrafish toxicity profiles are strikingly similar. This transparent vertebrate offers several compelling experimental advantages, including convenient drug delivery and low cost. Although full validation will require assessment of a large number of compounds from diverse classes, zebrafish can be used to eliminate potentially unsafe compounds rapidly in the early stages of drug development and to prioritize compounds for further preclinical and clinical studies. Adaptation of conventional instrumentation combined with new nanotechnology developments will continue to expand use of zebrafish for drug screening.

Section snippets

Cardiotoxicity assessment in zebrafish

Unforeseen cardiotoxicity is a major problem that can result in drug withdrawal. In 2004, rofecoxib (Vioxx), Merck's blockbuster antiarthritic drug was removed from the market because of increased risk of heart attack and stroke. Another example, propulsid (Cisapride), an oral gastrointestinal prokinetic agent, has been associated with ∼400 adverse cardiac events (arrhythmias) and has resulted in more than 80 deaths in the USA 6, 7. These problems with cardiotoxicity led to the removal of

Hepatotoxicity assessment in zebrafish

Drug-induced liver injury has been recognized by the pharmaceutical industry as a major toxicological problem. Tests that are useful for evaluating drug-induced hepatotoxicity in laboratory animals fall into four primary categories: (1) serum enzyme tests; (2) hepatic excretory tests; (3) assessment of alterations in the chemical constituents of the liver and (4) histological analysis. Tests for assessing repair and recovery of liver parenchyma and apoptosis are also used to study the effects

Neurotoxicity assessment in zebrafish

Neurotoxicity is another leading cause of drug withdrawal and examples of costly high-profile cases of neurotoxicity include diamthazole, vinyl chloride and clioquinol [29]. Neurotoxicity profiles of numerous approved drugs are incomplete and many cause neurotoxic side effects 29, 30, 31. Increasing public concern about drug- and chemical-induced neurotoxicity and the inadequacy of current toxicological testing requirements resulted in initiation of a US Congressional review of Federal research

Developmental toxicity assessment in zebrafish

After the teratogenic effects of thalidomide were recognized in 1966, the FDA established protocols to be used for assessing drug effects on reproduction and development before approval for human use. In addition, because of concerns about chemicals in human food, the EPA issued similar guidelines for pesticides in 1982 and for industrial chemicals in 1985. According to current international guidelines, developmental toxicity testing involves exposing pregnant animals, usually rats or rabbits,

Summary

Zebrafish has been shown to be a predictive animal model for assessing drug toxicity and safety. Assessment of a large number of compounds from diverse drug classes is necessary to further validate the model. Although it is unclear how ADME after drug delivery in fish water compares to ADME after delivery by other routes of administration, performance of studies in adult zebrafish using conventional drug delivery methods such as injection and intubation promises to increase the use of this

Conflict of interest

Both authors are employees of Phylonix. Ms McGrath is also an inventor of patents assigned to Phylonix.

References (60)

  • T. Bresolin

    Expression of PXR, CYP3A and MDR1 genes in liver of zebrafish

    Comp. Biochem. Physiol. C: Toxicol. Pharmacol.

    (2005)
  • H.P. Tseng

    Constitutive and xenobiotics-induced expression of a novel CYP3A gene from zebrafish larva

    Toxicol. Appl. Pharmacol.

    (2005)
  • C.Q. Li

    Whole zebrafish cytochrome P450 microplate assays for assessing drug metabolism and drug safety

    Toxicologist

    (2008)
  • T.G. Braunbeck

    Hepatic steatosis in zebrafish (Brachydanio rerio) induced by long-term exposure to gamma-hexachlorocyclohexane

    Ecotoxicol. Environ. Saf.

    (1990)
  • J. Ninkovic et al.

    The zebrafish as a model system for assessing the reinforcing properties of drugs of abuse

    Methods

    (2006)
  • C. Parng

    Neurotoxicity assessment using zebrafish

    J. Pharmacol. Toxicol. Methods

    (2007)
  • C. Parng

    A zebrafish assay for identifying neuroprotectants in vivo

    Neurotoxicol. Teratol.

    (2006)
  • A. Seoane

    Degeneration and gliosis in rat retina and central nervous system following 3,3″-iminodipropionitrile exposure

    Brain Res.

    (1999)
  • A.L. Nielsen et al.

    Structural and functional characterization of the zebrafish gene for glial fibrillary acidic protein, GFAP

    Gene

    (2003)
  • G.R. Breese

    The neonate-6-hydroxydopamine-lesioned rat: a model for clinical neuroscience and neurobiological principles

    Brain Res. Brain Res. Rev.

    (2005)
  • E. Rink et al.

    The teleostean (zebrafish) dopaminergic system ascending to the subpallium (striatum) is located in the basal diencephalons (posterior tuberculum)

    Brain Res.

    (2001)
  • E. Rink et al.

    Connections of the ventral telencephalon and tyrosine hydroxylase distribution in the zebrafish brain (Danio rerio) lead to identification of an ascending dopaminergic system in a teleost

    Brain Res. Bull.

    (2002)
  • C. Charriaut-Marlangue

    Apoptosis: a target for neuroprotection

    Therapie

    (2004)
  • S. Mielke

    Peripheral neuropathy: a persisting challenge in paclitaxel-based regimes

    Eur. J. Cancer

    (2006)
  • S.C. Baraban

    Pentylenetetrazole induced changes in zebrafish behavior, neural activity and c-fos expression

    Neuroscience

    (2005)
  • C. Parng

    Zebrafish: a preclinical model for drug screening

    Assay Drug Dev. Technol.

    (2002)
  • C. Parng

    In vivo zebrafish assays for toxicity testing

    Curr. Opin. Drug Discov. Dev.

    (2005)
  • M. Haldi

    Human melanoma cells transplanted into zebrafish proliferate, migrate, produce melanin, form masses and stimulate angiogenesis in zebrafish

    Angiogenesis

    (2006)
  • C. Thisse et al.

    Organogenesis – heart and blood formation from the zebrafish point of view

    Science

    (2002)
  • D. Sedmera

    Functional and morphological evidence for a ventricular conduction system in zebrafish and Xenopus hearts

    Am. J. Physiol. Heart Circ. Physiol.

    (2003)
  • Cited by (451)

    • N-nitrosodimethylamine exposure to zebrafish embryos/larvae causes cardiac and spinal developmental toxicity

      2024, Comparative Biochemistry and Physiology Part - C: Toxicology and Pharmacology
    View all citing articles on Scopus
    View full text