Modeling Human Nonalcoholic Steatohepatitis-Associated Changes in Drug Transporter Expression Using Experimental Rodent Models
Modeling Human Nonalcoholic Steatohepatitis-Associated Changes in Drug Transporter Expression Using Experimental Rodent Models
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DOI：
10.1124/dmd.113.055996
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发表时间：
2014-04-01
影响因子：
3.9
通讯作者：
Cherrington, Nathan J.
中科院分区：
文献类型：
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作者：
Canet, Mark J.;Hardwick, Rhiannon N.;Cherrington, Nathan J.
非酒精性脂肪性肝病是一种常见的慢性肝病，可进展为非酒精性脂肪性肝炎（NASH）的晚期阶段。NASH已被证明可以改变药物转运蛋白的调节，并可能影响药物不良反应的发生。已经提出了几种实验啮齿动物模型来研究NASH，但没有一个模型完全概括了人类疾病的所有方面。本研究的目的是确定哪种实验NASH模型最能反映人类药物转运蛋白表达的已知改变，以实现NASH中更准确的药物处置预测。本研究中使用了大鼠和小鼠NASH模型，包括蛋氨酸和胆碱缺乏（MCD）饮食模型、致动脉粥样硬化饮食模型、ob/ob和db/db小鼠以及fa/fa大鼠。病理评分评价表明，MCD和致动脉粥样硬化大鼠以及ob/ob和db/db小鼠发生NASH。药物转运蛋白的肝脏mRNA和蛋白表达分析表明，一般而言，在大鼠MCD和小鼠ob/ob和db/db模型中，外排转运蛋白被诱导，摄取转运蛋白被抑制。最后，一致性分析表明，小鼠和大鼠MCD模型以及小鼠ob/ob和db/db NASH模型与人转运蛋白mRNA和蛋白表达最相似。这些结果表明，MCD大鼠和小鼠模型以及ob/ob和db/db小鼠模型可能有助于预测药物在人类和啮齿类动物中具有相似动力学的分布改变。
Nonalcoholic fatty liver disease is a prevalent form of chronic liver disease that can progress to the more advanced stage of nonalcoholic steatohepatitis (NASH). NASH has been shown to alter drug transporter regulation and may have implications in the development of adverse drug reactions. Several experimental rodent models have been proposed for the study of NASH, but no single model fully recapitulates all aspects of the human disease. The purpose of the current study was to determine which experimental NASH model best reflects the known alterations in human drug transporter expression to enable more accurate drug disposition predictions in NASH. Both rat and mouse NASH models were used in this investigation and include the methionine and choline deficient (MCD) diet model, atherogenic diet model, ob/ob and db/db mice, and fa/fa rats. Pathologic scoring evaluations demonstrated that MCD and atherogenic rats, as well as ob/ob and db/db mice, developed NASH. Liver mRNA and protein expression analyses of drug transporters showed that in general, efflux transporters were induced and uptake transporters were repressed in the rat MCD and the mouse ob/ob and db/db models. Lastly, concordance analyses suggest that both the mouse and rat MCD models as well as mouse ob/ob and db/db NASH models show the most similarity to human transporter mRNA and protein expression. These results suggest that the MCD rat and mouse model, as well as the ob/ob and db/db mouse models, may be useful for predicting altered disposition of drugs with similar kinetics across humans and rodents.