Department of Biomedical and Pharmaceutical Sciences, University of Rhode Island, Kingston, RI 02881, USA.
Drug Metab Dispos. 2011 Jun;39(6):992-9. doi: 10.1124/dmd.110.037507. Epub 2011 Mar 23.
Drug pharmacokinetics can be altered in obese and diabetic subjects. In consideration of the prevalence of obesity and diabetes, characterization of transporter expression in mouse models of diabetes and obesity may be a useful tool to aid in prediction of altered drug pharmacokinetics or adverse drug reactions. It has been reported that ob/ob mice, which display a severe obesity and diabetes phenotype, exhibit multiple changes in drug transporter expression in liver and kidney. In the present study, the mRNA and protein expression of major drug transporters was determined in livers and kidneys of diet-induced obese (DIO) C57BL/6J male mice. The mice were fed a high-fat diet (HFD) (60% fat) from 6 weeks of age and display obesity, fatty liver, and mild hyperglycemia. The HFD diet increased expression of multidrug resistance-associated proteins Abcc3 and 4 mRNA and protein in liver by 3.4- and 1.4-fold, respectively, compared with that detected in control mice fed a low-fat diet (LFD). In contrast, Abcc1 mRNA and protein decreased by 50% in livers of DIO mice compared with those in livers to lean mice. The HFD did not alter transporter expression in kidney compared with the LFD. In summary, unlike ob/ob and db/db mice, DIO mice exhibited a selective induction of efflux transporter expression in liver (i.e., Abcc3 and 4). In addition, diet-induced obesity affects transporter expression in liver but not kidney in the C57BL/6J mouse model. These data indicate that hepatic transporter expression is only slightly altered in a model of mild diabetes and nonalcoholic fatty liver disease and obesity.
肥胖和糖尿病患者的药物药代动力学可能会发生改变。鉴于肥胖和糖尿病的普遍性，对糖尿病和肥胖症小鼠模型中转运体表达的特征描述可能是一种有用的工具，有助于预测药物药代动力学的改变或药物不良反应。据报道，ob/ob 小鼠表现出严重的肥胖和糖尿病表型，其肝脏和肾脏中的药物转运体表达发生了多种变化。在本研究中，测定了饮食诱导肥胖（DIO）C57BL/6J 雄性小鼠肝脏和肾脏中主要药物转运体的 mRNA 和蛋白表达。这些小鼠从 6 周龄开始喂食高脂肪饮食（HFD）（60%脂肪），表现出肥胖、脂肪肝和轻度高血糖。与低脂饮食（LFD）喂养的对照小鼠相比，HFD 饮食使肝脏中多药耐药相关蛋白 Abcc3 和 4 的 mRNA 和蛋白表达分别增加了 3.4 倍和 1.4 倍。相比之下，与瘦鼠肝脏中的 Abcc1 mRNA 和蛋白相比，DIO 小鼠肝脏中的 Abcc1 mRNA 和蛋白减少了 50%。HFD 与 LFD 相比，并未改变肾脏中转运体的表达。总之，与 ob/ob 和 db/db 小鼠不同，DIO 小鼠肝脏中仅选择性诱导了外排转运体的表达（即 Abcc3 和 4）。此外，饮食诱导的肥胖症影响 C57BL/6J 小鼠模型中肝脏而非肾脏中转运体的表达。这些数据表明，在轻度糖尿病和非酒精性脂肪肝和肥胖症模型中，肝脏转运体的表达仅略有改变。
