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建立并使用同时过表达UGT1A1和MRP2的新型MDCK II细胞，以通过葡萄糖醛酸化途径表征类黄酮代谢。

Establishment and use of new MDCK II cells overexpressing both UGT1A1 and MRP2 to characterize flavonoid metabolism via the glucuronidation pathway.

作者信息

Wang Meifang, Yang Guangyi, He Yu, Xu Beibei, Zeng Min, Ge Shufan, Yin Taijun, Gao Song, Hu Ming

机构信息

Hubei University of Medicine and University-Affiliated Taihe Hospital, Shiyan, China.

Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy, University of Houston, Houston, TX, USA.

出版信息

Mol Nutr Food Res. 2016 Sep;60(9):1967-83. doi: 10.1002/mnfr.201500321. Epub 2016 Jul 6.

DOI:10.1002/mnfr.201500321
PMID:26833852
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC5358013/
Abstract

SCOPE

The purpose of this study is to characterize how overexpression of an efflux transporter and an UDP-glucuronosyltransferase (UGT) affects the cellular kinetics of glucuronidation processes.

METHODS AND RESULTS

A new MDCK II cell line overexpressing both MRP2 and UGT1A1 (MDCKII-UGT1A1/MRP2 cells) was developed and used to determine how overexpression of an efflux transporter affects the kinetics of cellular flavonoid glucuronide production. The results showed that most model flavonoids (from a total of 13) were mainly metabolized into glucuronides in the MDCKII-UGT1A1/MRP2 cells and the glucuronides were rapidly excreted. Flavonoids with three or fewer hydroxyl group at 7, 3' or 6 hydroxyl group were also metabolized into sulfates. Mechanistic studies using 7-hydroxylflavone showed that its glucuronide was mainly (90%) effluxed by BCRP with a small (10%) but significant contribution from MRP2. Maximal velocity of glucuronide production MDCK-MRP2/UGT1A1 cells showed a fairly good correlation (R(2) >0.8) with those derived using UGT1A1 microsomes, but other kinetic parameters (e.g., Km ) did not correlate.

CONCLUSION

Overexpression of a second efficient efflux transporter did not significantly change the fact that BCRP is the dominant transporter for flavonoid glucuronide nor did it diminish the influence of the efflux transporter as the "gate keeper" of glucuronidation process.

摘要

范围

本研究的目的是描述外排转运蛋白和尿苷二磷酸葡萄糖醛酸基转移酶（UGT）的过表达如何影响葡萄糖醛酸化过程的细胞动力学。

方法与结果

构建了一种同时过表达多药耐药相关蛋白2（MRP2）和UGT1A1的新型MDCK II细胞系（MDCKII-UGT1A1/MRP2细胞），并用于确定外排转运蛋白的过表达如何影响细胞中黄酮类葡萄糖醛酸苷生成的动力学。结果表明，大多数模型黄酮类化合物（共13种）在MDCKII-UGT1A1/MRP2细胞中主要代谢为葡萄糖醛酸苷，且葡萄糖醛酸苷迅速排出。在7、3'或6位羟基上具有三个或更少羟基的黄酮类化合物也代谢为硫酸盐。使用7-羟基黄酮的机制研究表明，其葡萄糖醛酸苷主要（90%）由乳腺癌耐药蛋白（BCRP）外排，多药耐药相关蛋白2（MRP2）的贡献较小（10%）但具有显著性。MDCK-MRP2/UGT1A1细胞中葡萄糖醛酸苷生成的最大速度与使用UGT1A1微粒体得到的结果显示出相当好的相关性（R(2)>0.8），但其他动力学参数（如Km）则无相关性。

结论

第二种高效外排转运蛋白的过表达并未显著改变BCRP是黄酮类葡萄糖醛酸苷主要转运蛋白这一事实，也未削弱外排转运蛋白作为葡萄糖醛酸化过程“守门人”的影响。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/df32/5358013/6fef0dd74632/nihms817945f8a.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/df32/5358013/55170aa211f7/nihms817945f3.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/df32/5358013/a61fad647553/nihms817945f5a.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/df32/5358013/60e30444e3e1/nihms817945f6a.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/df32/5358013/fb4e501b3743/nihms817945f7a.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/df32/5358013/0f7d77af7f14/nihms817945f1a.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/df32/5358013/12dc2468c187/nihms817945f2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/df32/5358013/55170aa211f7/nihms817945f3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/df32/5358013/c8f7ec45a757/nihms817945f4a.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/df32/5358013/a61fad647553/nihms817945f5a.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/df32/5358013/60e30444e3e1/nihms817945f6a.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/df32/5358013/6fef0dd74632/nihms817945f8a.jpg

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[UDP-glucuronyltransferases in detoxification and activation metabolism of endogenous compounds and xenobiotics].[尿苷二磷酸葡萄糖醛酸基转移酶在内源性化合物和外源性物质的解毒及活化代谢中的作用]
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Sulfation of selected mono-hydroxyflavones by sulfotransferases in vitro: a species and gender comparison.体外研究磺基转移酶对几种单羟基黄酮类化合物的硫酸化作用：种属和性别比较。
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