Profiles and Gender-Specifics of UDP-Glucuronosyltransferases and Sulfotransferases Expressions in the Major Metabolic Organs of Wild-Type and Efflux Transporter Knockout FVB Mice
Profiles and Gender-Specifics of UDP-Glucuronosyltransferases and Sulfotransferases Expressions in the Major Metabolic Organs of Wild-Type and Efflux Transporter Knockout FVB Mice
复制标题
野生型和外排转运蛋白敲除 FVB 小鼠主要代谢器官中 UDP-葡萄糖醛酸基转移酶和磺基转移酶表达的概况和性别特异性
DOI：
10.1021/acs.molpharmaceut.7b00435
复制
发表时间：
2017-09-01
影响因子：
4.9
通讯作者：
Liu, Zhongqiu
中科院分区：
文献类型：
--
作者：
Chen, Jiamei;Zheng, Haihui;Liu, Zhongqiu
肝和肝外组织通过UDP-葡萄糖醛酸基转移酶（UGT/Ugts）和磺基转移酶（SULT/Suts）参与外源性物质解毒、致癌物活化、前药加工和雌激素调节。野生型（WT）和外排转运蛋白敲除（KO）FVB小鼠通常用于进行药代动力学、代谢和毒性研究。我们采用开发的LTHPLC-MS/MS方法获得系统的洞察性别特异性的Ugts和SULT在主要代谢器官。结果表明，Ugts/Sults在肝脏中含量最高，其次是小肠和肾脏。在肝脏中，Ugt 2bS、Ugt 2b 1、Ugtla 6a、Ugt 1a 1、Sult 1a 1和Sult 1d 1是主要的同种型。雄性外排转运蛋白KO小鼠中Ugt 1a 9的蛋白量显著高于WT小鼠，而雌性外排转运蛋白KO小鼠中Ugt 1aS和Sult 1a 1的蛋白量严重降低。在WT和外排转运蛋白KO小鼠中，Ugt 1a 1、Ugt 1a 5、Sult 1a 1、Sult 1d 1和Sult 3a 1的表达水平具有雌性特异性，而Ugt 2b 1、Ugt 2b 5和Ugt 2b 36的表达水平具有雄性特异性。在小肠中，Ugt 1a 1、Sult 1b 1和Sult 2b 1是主要的同种型。KO Mdr 1a、Bcrp 1、Mrp 1、Mrp 2和Mdr 1a对Ugts/Sut的蛋白水平和性别差异均有明显影响。外排转运蛋白的KO影响肾脏、心脏和脾脏中Ugts/Sults的蛋白量。因此，更好地了解WT和外排转运蛋白KO小鼠主要代谢器官中Ugts和Suts的表达谱和性别特异性，有助于评价相应底物的潜在疗效和毒性。
Hepatic and extrahepatic tissues participate in xenobiotic detoxication, carcinogen activation, prodrug processing, and estrogen regulation through UDP-glucuronosyltransferases (UGTs/Ugts) and sulfotransferases (SULTs/Sults). Wild-type (WT) and efflux transporter knockout (KO) FVB mice have been commonly used to perform the studies of pharmacokinetics, metabolism, and toxicity. We employed the developed LTHPLC-MS/MS approach to gain systematic insight on gender-specific of Ugts and Sults in major metabolic organs. Results showed that the liver was the most abundant with Ugts/Sults, followed by the small intestine and the kidney. In the liver, Ugt2bS, Ugt2b1, Ugtla6a, Ugt1a1, Sult1a1, and Sult1d1 were the major isoforms. The protein amounts of Ugt1a9 were significantly higher in male efflux transporter KO mice than in WT mice, whereas Ugt1aS and Sult1a1 severely decreased in female efflux transporter KO mice. In WT and efflux transporter KO mice, the expression levels of Ugt1a1, Ugt1a5, Sult1a1, Sult1d1, and Sult3a1 were female-specific, whereas those of Ugt2b1, Ugt2b5, and Ugt2b36 were male-specific. In the small intestine, Ugt1a1, Sult1b1, and Sult2b1 were the major isofonns. The protein levels and gender differences of Ugts/Sults were obviously affected when KO of Mdr1a, and Bcrp1, Mrp1, Mrp2, and Mdr1a, respectively. The KO of efflux transporter affected the protein amounts of Ugts/Sults in the kidney, heart, and spleen. Therefore, a better understanding of the expression profiles and gender-specific of Ugts and Sults in major metabolic organs of WT and efflux transporter KO mice is useful for the evaluation of potential efficacy, and toxicity of corresponding substrates.