Foster John R, Jacobsen Matt, Kenna Gerry, Schulz-Utermoehl Timothy, Morikawa Yoshio, Salmu Juuso, Wilson Ian D
Safety Assessment, AstraZeneca UK Ltd, Macclesfield, Cheshire, UK.
Toxicol Pathol. 2012 Dec;40(8):1106-16. doi: 10.1177/0192623312447542. Epub 2012 Jun 6.
The aims of this study were to assess the utility of the PXB mouse model of a chimeric human/mouse liver in studying human-specific effects of an important human hepatotoxic drug, the PPARγ agonist, troglitazone. When given orally by gavage for 7 days, at dose levels of 300 and 600 ppm, troglitazone induced specific changes in the human hepatocytes of the chimeric liver without an effect on the murine hepatic portions. The human hepatocytes, in the vehicle-treated PXB mouse, showed an accumulation of electron-dense lipid droplets that appeared as clear vacuoles under the light microscope in H&E-stained sections. Following dosing with troglitazone, there was a loss of the large lipid droplets in the human hepatocytes, a decrease in the amount of lipid as observed in frozen sections of liver stained by Oil-red-O, and a decrease in the expression of two bile acid transporters, BSEP and MRP2. None of these changes were observed in the murine remnants of the chimeric liver. No changes were observed in the expression of three CYPs, CYP 3A2, CYP 1A1, and CYP 2B1, in either the human or murine hepatocytes, even though the baseline expression of the enzymes differed significantly between the two hepatocyte species with the mouse hepatocytes consistently showing increased expression of the protein of all three enzymes. This study has shown that the human hepatocytes, in the PXB chimeric mouse liver, retain an essentially normal phenotype in the mouse liver and, the albeit limited CYP enzymes studied show a more human, rather than a murine, expression pattern. In line with this conclusion, the study has shown a differential response of the human versus the mouse hepatocytes, and the effects observed are highly suggestive of a differential handling of the compound by the two hepatocyte species although the exact reasons are not as yet clear. The PXB chimeric mouse system therefore holds the clear potential to explore human hepatic-specific features, such as metabolism, prior to dosing human subjects, and as such should have considerable utility in drug discovery and development.
本研究的目的是评估人/鼠嵌合肝脏的PXB小鼠模型在研究一种重要的人类肝毒性药物（PPARγ激动剂曲格列酮）的人类特异性效应方面的效用。当以300和600 ppm的剂量水平经口灌胃给药7天时，曲格列酮在嵌合肝脏的人肝细胞中诱导了特异性变化，而对鼠肝部分没有影响。在接受载体处理的PXB小鼠中，人肝细胞显示出电子致密脂滴的积累，在苏木精和伊红（H&E）染色切片的光学显微镜下呈现为透明空泡。用曲格列酮给药后，人肝细胞中的大脂滴减少，在油红O染色的肝脏冰冻切片中观察到脂质含量降低，并且两种胆汁酸转运蛋白BSEP和MRP2的表达减少。在嵌合肝脏的鼠肝残余部分未观察到这些变化。在人或鼠肝细胞中，三种细胞色素P450（CYP），即CYP 3A2、CYP 1A1和CYP 2B1的表达均未发生变化，尽管这两种肝细胞中这些酶的基线表达存在显著差异，小鼠肝细胞中这三种酶的蛋白表达始终增加。本研究表明，PXB嵌合小鼠肝脏中的人肝细胞在小鼠肝脏中保持基本正常的表型，并且尽管所研究的CYP酶有限，但显示出更接近人类而非小鼠的表达模式。与这一结论一致，该研究显示了人肝细胞与小鼠肝细胞的不同反应，观察到的效应高度提示这两种肝细胞对该化合物的处理方式不同，尽管确切原因尚不清楚。因此，PXB嵌合小鼠系统在给人类受试者给药之前具有探索人类肝脏特异性特征（如代谢）的明显潜力，因此在药物发现和开发中应具有相当大的效用。
