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Drug-metabolizing Enzyme, Transporter, and Nuclear Receptor Genetically Modified Mouse Models

Overview
Journal Drug Metab Rev
Publisher Informa Healthcare
Specialty Pharmacology
Date 2010 Sep 22
PMID 20854191
Citations 16
Authors
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Abstract

Determining the in vivo significance of a specific enzyme, transporter, or xenobiotic receptor in drug metabolism and pharmacokinetics may be hampered by gene multiplicity and complexity, levels of expression, and interaction between various components involved. The development of knockout (loss-of-function) and transgenic (gain-of-function) mouse models opens the door to the improved understanding of gene function in a whole-body system. There is also growing interest in the development of humanized mice to overcome species differences in drug metabolism and disposition. This review, therefore, aims to summarize and discuss some successful examples of drug-metabolizing enzyme, transporter, and nuclear-receptor genetically modified mouse models. These genetically modified mouse models have been proven as invaluable models for understanding in vivo function of drug-metabolizing enzymes, transporters, and xenobiotic receptors in drug metabolism and transport, as well as predicting potential drug-drug interaction and toxicity in humans. Nevertheless, concerns remain about interpretation of data obtained from such genetically modified mouse models, in which the expression of related genes is altered significantly.

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References
1.
Fang C, Behr M, Xie F, Lu S, Doret M, Luo H . Mechanism of chloroform-induced renal toxicity: non-involvement of hepatic cytochrome P450-dependent metabolism. Toxicol Appl Pharmacol. 2007; 227(1):48-55. PMC: 2274901. DOI: 10.1016/j.taap.2007.10.014. View

2.
Tsuda M, Terada T, Mizuno T, Katsura T, Shimakura J, Inui K . Targeted disruption of the multidrug and toxin extrusion 1 (mate1) gene in mice reduces renal secretion of metformin. Mol Pharmacol. 2009; 75(6):1280-6. DOI: 10.1124/mol.109.056242. View

3.
Conklin D, Haberzettl P, Prough R, Bhatnagar A . Glutathione-S-transferase P protects against endothelial dysfunction induced by exposure to tobacco smoke. Am J Physiol Heart Circ Physiol. 2009; 296(5):H1586-97. PMC: 2685347. DOI: 10.1152/ajpheart.00867.2008. View

4.
Xia C, Milton M, Gan L . Evaluation of drug-transporter interactions using in vitro and in vivo models. Curr Drug Metab. 2007; 8(4):341-63. DOI: 10.2174/138920007780655423. View

5.
Nguyen N, Bonzo J, Chen S, Chouinard S, Kelner M, Hardiman G . Disruption of the ugt1 locus in mice resembles human Crigler-Najjar type I disease. J Biol Chem. 2008; 283(12):7901-11. DOI: 10.1074/jbc.M709244200. View