Current Drug Metabolism

Michael Sinz
Bristol Myers Squibb
Wallingford, CT
USA

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

Author(s): Jiunn H. Lin

Affiliation: Department of Drug Metabolism&Pharmacokinetics, Merck Research Laboratories, West Point, Pennsylvania USA.

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

Abstract:

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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Article Details

VOLUME: 9
ISSUE: 5
Page: [419 - 438]
Pages: 20
DOI: 10.2174/138920008784746355