Severe diabetes and leptin resistance cause differential hepatic and renal transporter expression in mice.
Severe diabetes and leptin resistance cause differential hepatic and renal transporter expression in mice.
复制标题
严重的糖尿病和瘦素耐药性在小鼠中导致肝脏和肾脏转运蛋白的差异。
DOI：
10.1186/1476-5926-11-1
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发表时间：
2012-04-23
期刊：
影响因子：
--
通讯作者：
Slitt AL
中科院分区：
文献类型：
--
作者：
More VR;Wen X;Thomas PE;Aleksunes LM;Slitt AL
2型糖尿病在美国和其他西方国家是一个主要的健康问题，患病率每年都在增加。有必要更好地建模和预测药物不良反应，药物诱导的肝损伤和药物疗效在这一人群中。由于转运蛋白对药物清除和处置有显著贡献，因此确定严重糖尿病表型是否改变药物转运蛋白表达以及糖尿病小鼠模型是否改变了对乙酰氨基酚（APAP）代谢物的处置是非常重要的。在成年C57 BKS和db/db小鼠的肝脏和肾脏中定量转运蛋白mRNA和蛋白质表达，这些小鼠由于缺乏功能性瘦素受体而具有严重的糖尿病表型。还测定了对乙酰氨基酚-葡糖苷酸（多药耐药相关蛋白转运蛋白的底物）的尿排泄。db/db小鼠主要摄取转运蛋白如肝和肾中的有机阴离子转运多肽Slco 1a 1、肝中的1a 4和肾中的Slc 22 a7的mRNA表达降低。相比之下，与C57 BKS对照相比，db/db雄性小鼠肝脏中Abcc 3和4 mRNA和蛋白质表达高出2倍以上。db/db小鼠中APAP-葡糖苷酸、-硫酸盐和N-乙酰半胱氨酸代谢产物的尿液水平较高。严重的糖尿病表型/表现显著改变了肝脏和肾脏中的药物转运蛋白表达，这与尿APAP代谢物水平相对应。
Type-2 Diabetes is a major health concern in the United States and other Westernized countries, with prevalence increasing yearly. There is a need to better model and predict adverse drug reactions, drug-induced liver injury, and drug efficacy in this population. Because transporters significantly contribute to drug clearance and disposition, it is highly significant to determine whether a severe diabetes phenotype alters drug transporter expression, and whether diabetic mouse models have altered disposition of acetaminophen (APAP) metabolites. Transporter mRNA and protein expression were quantified in livers and kidneys of adult C57BKS and db/db mice, which have a severe diabetes phenotype due to a lack of a functional leptin receptor. The urinary excretion of acetaminophen-glucuronide, a substrate for multidrug resistance-associated proteins transporters was also determined. The mRNA expression of major uptake transporters, such as organic anion transporting polypeptide Slco1a1 in liver and kidney, 1a4 in liver, and Slc22a7 in kidney was decreased in db/db mice. In contrast, Abcc3 and 4 mRNA and protein expression was more than 2 fold higher in db/db male mouse livers as compared to C57BKS controls. Urine levels of APAP-glucuronide, -sulfate, and N-acetyl cysteine metabolites were higher in db/db mice. A severe diabetes phenotype/presentation significantly altered drug transporter expression in liver and kidney, which corresponded with urinary APAP metabolite levels.