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年龄和基因型依赖性变化对人肝内 6 种主要尿苷二磷酸葡萄糖醛酸基转移酶的蛋白丰度和活性的影响。

Age- and Genotype-Dependent Variability in the Protein Abundance and Activity of Six Major Uridine Diphosphate-Glucuronosyltransferases in Human Liver.

机构信息

Department of Pharmaceutics, University of Washington, Seattle, Washington, USA.

Division of Clinical Pharmacology, Toxicology & Therapeutic Innovation, Children's Mercy-Kansas City, Missouri, and School of Medicine, University of Missouri-Kansas City, Kansas City, Missouri, USA.

出版信息

Clin Pharmacol Ther. 2019 Jan;105(1):131-141. doi: 10.1002/cpt.1109. Epub 2018 Jul 12.

Abstract

The ontogeny of hepatic uridine diphosphate-glucuronosyltransferases (UGTs) was investigated by determining their protein abundance in human liver microsomes isolated from 136 pediatric (0-18 years) and 35 adult (age >18 years) donors using liquid chromatography / tandem mass spectrometry (LC-MS/MS) proteomics. Microsomal protein abundances of UGT1A1, UGT1A4, UGT1A6, UGT1A9, UGT2B7, and UGT2B15 increased by ∼8, 55, 35, 33, 8, and 3-fold from neonates to adults, respectively. The estimated age at which 50% of the adult protein abundance is observed for these UGT isoforms was between 2.6-10.3 years. Measured in vitro activity was generally consistent with the protein data. UGT1A1 protein abundance was associated with multiple single nucleotide polymorphisms exhibiting noticeable ontogeny-genotype interplay. UGT2B15 rs1902023 (*2) was associated with decreased protein activity without any change in protein abundance. Taken together, these data are invaluable to facilitate the prediction of drug disposition in children using physiologically based pharmacokinetic modeling as demonstrated here for zidovudine and morphine.

摘要

本研究采用液相色谱-串联质谱(LC-MS/MS)蛋白质组学方法,测定了 136 名儿科(0-18 岁)和 35 名成人(>18 岁)供体肝微粒体中尿苷二磷酸葡萄糖醛酸基转移酶(UGTs)的蛋白丰度,以此研究其肝内的个体发育过程。UGT1A1、UGT1A4、UGT1A6、UGT1A9、UGT2B7 和 UGT2B15 的微粒体蛋白丰度分别在新生儿至成人阶段增加了约 8、55、35、33、8 和 3 倍。这些 UGT 同工型中,预计达到成人蛋白丰度 50%的年龄分别为 2.6-10.3 岁。体外测定的活性通常与蛋白数据一致。UGT1A1 蛋白丰度与多个单核苷酸多态性相关,这些多态性表现出明显的个体发育-基因型相互作用。UGT2B15 rs1902023(*2) 与蛋白活性降低相关,而蛋白丰度没有变化。综上所述,这些数据对于使用基于生理的药代动力学模型预测儿童药物处置非常有价值,本文以齐多夫定和吗啡为例进行了说明。

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