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Applications and Limitations of Genetically Modified Mouse Models in Drug Discovery and Development

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Genetically modified mouse models in which a specific gene is removed or replaced have proven to be powerful tools for identification/validation of target gene and scientific understanding of molecular mechanisms underlying drug-induced toxicity through mechanistic studies. In spite of the advantage, there are significant limitations of genetically modified mouse models. Modification of a given gene does not always result in the anticipated phenotype. In some instances, phenotypes of targeted mouse mutants were not those predicted from the presumed function of the given genes, while other null mutants revealed no apparent defects. Furthermore, the phenotypic outcome can be influenced by many environmental and genetic factors. Therefore, interpretation of the significance of the findings from studies using genetically modified mouse models is not always as straightforward as one would expect, especially when desire is to extrapolate the findings to humans. Interestingly, many humanized mouse models have been generated for evaluating the function and regulation of cytochrome P450 (CYP) enzymes. Our fascination with humanized animals dates back to ancients. For example, the Great Sphinx of Giza, a large half-human and half-lion statue, is believed to have been built by Egyptians about 4500 years ago. Although the creation of humanized animals that carry a particular human CYP gene provides useful tools for scientific understanding of the function and regulation of the CYP enzyme, these humanized mouse models are not so useful in prediction of human pharmacokinetics in a quantitative sense. Accordingly, it is important to keep in mind that an animal engineered to express a human gene and its protein is still an animal.

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Keywords: Aryl hydrocarbon receptor (AhR); Constitutive androstane receptor (CAR); Cytochrome P450 (CYP); Genetically modified mouse models; Humanized mouse models; Peroxisome proliferatoractivated receptor (PPAR); Pregnane X receptor (PXR); influx and efflux transporters

Document Type: Research Article

Publication date: June 1, 2008

More about this publication?
  • Current Drug Metabolism aims to cover all the latest and outstanding developments in drug metabolism and disposition. The journal serves as an international forum for the publication of timely reviews in drug metabolism. Current Drug Metabolism is an essential journal for academic, clinical, government and pharmaceutical scientists who wish to be kept informed and up-to-date with the latest and most important developments. The journal covers the following areas:

    In vitro systems including CYP-450; enzyme induction and inhibition; drug-drug interactions and enzyme kinetics; pharmacokinetics, toxicokinetics, species scaling and extrapolations; P-glycoprotein and transport carriers; target organ toxicity and interindividual variability; drug metabolism and disposition studies; extrahepatic metabolism; phase I and phase II metabolism; recent developments for the identification of drug metabolites and adducts.
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