Abstract
Cytochrome P450s (P450s) are important enzymes involved in the metabolism of xenobiotics, particularly clinically used drugs, and are also responsible for metabolic activation of chemical carcinogens and toxins. Many xenobiotics can activate nuclear receptors that in turn induce the expression of genes encoding xenobiotic metabolizing enzymes and drug transporters. Marked species differences in the expression and regulation of cytochromes P450 and xenobiotic nuclear receptors exist. Thus, obtaining reliable rodent models to accurately reflect human drug and carcinogen metabolism is severely limited. Humanized transgenic mice were developed in an effort to create more reliable in vivo systems to study and predict human responses to xenobiotics. Human P450s or human xenobiotic-activated nuclear receptors were introduced directly or replaced the corresponding mouse gene, thus creating “humanized” transgenic mice. Mice expressing human CYP1A1/CYP1A2, CYP2E1, CYP2D6, CYP3A4, CY3A7, pregnane X receptor, and peroxisome proliferator-activated receptor α were generated and characterized. These humanized mouse models offer a broad utility in the evaluation and prediction of toxicological risk that may aid in the development of safer drugs.
Footnotes
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Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
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doi:10.1124/jpet.108.141242.
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ABBREVIATIONS: P450s, cytochromes P450; PXR, pregnane X receptor; PPARα, peroxisome proliferator-activated receptor α; CAR, constitutive androstane receptor; PCN, pregnenolone-16α-carbonitrile; BAC, bacterial artificial chromosome; PAC, P1 phage artificial chromosome; AHR, arylhydrocarbon receptor; 3-MC, 3-methylcholanthrene; PhIP, 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine; APAP, acetaminophen; DDIs, drug-drug interactions; HIV, human immunodeficiency virus; Wy-14,643, [[4-chloro-6-[(2,3-dimethylphenyl)amino]-2-pyrimidinyl]thio]-acetic acid; m, mouse; h, human.
- Received May 16, 2008.
- Accepted August 4, 2008.
- The American Society for Pharmacology and Experimental Therapeutics
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