Humanized mouse lines and their application for prediction of human drug metabolism and toxicological risk assessment.
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 alpha 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.
Cheung
Connie
C
Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Building 37, Room 3106, 9000 Rockville Pike, Bethesda, MD 20892, USA.
Gonzalez
Frank J
FJ
D000818:Animals; D019363:Cytochrome P-450 CYP1A1 / Q000502:physiology; D019388:Cytochrome P-450 CYP1A2 / Q000502:physiology; D019389:Cytochrome P-450 CYP2D6 / Q000502:physiology; D019392:Cytochrome P-450 CYP2E1 / Q000502:physiology; D051544:Cytochrome P-450 CYP3A / Q000502:physiology; D003577:Cytochrome P-450 Enzyme System / Q000502:physiology*; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D047493:PPAR alpha / Q000502:physiology; D004364:Pharmaceutical Preparations / Q000378:metabolism*; D000077297:Pregnane X Receptor; D011987:Receptors, Steroid / Q000502:physiology; D018570:Risk Assessment; D013045:Species Specificity
D047493:PPAR alpha; D004364:Pharmaceutical Preparations; D000077297:Pregnane X Receptor; D011987:Receptors, Steroid; D003577:Cytochrome P-450 Enzyme System; D019392:Cytochrome P-450 CYP2E1; D019363:Cytochrome P-450 CYP1A1; D019388:Cytochrome P-450 CYP1A2; D019389:Cytochrome P-450 CYP2D6; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human