Variants in the CYP2B6 3'UTR Alter In Vitro and In Vivo CYP2B6 Activity: Potential Role of MicroRNAs.
Variants in the CYP2B6 3'UTR Alter In Vitro and In Vivo CYP2B6 Activity: Potential Role of MicroRNAs.
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DOI：
10.1002/cpt.892
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发表时间：
2018-07
影响因子：
6.7
通讯作者：
Skaar TC
中科院分区：
文献类型：
--
作者：
Burgess KS;Ipe J;Swart M;Metzger IF;Lu J;Gufford BT;Thong N;Desta Z;Gaedigk R;Pearce RE;Gaedigk A;Liu Y;Skaar TC
CYP2B6*6和CYP2B6*18是临床上最重要的导致CYP2B6蛋白表达和活性降低的变异体。然而，这些变异并不能解释CYP2B6活性的所有变异性。新出现的证据表明，3‘非编码区的遗传变异可能通过改变microRNA的调控来解释药物反应的变化。在健康志愿者中，5个3‘非编码区变异与Eefavirenz AUC0-48(8-OH-EFV/EFV)比值显著改变有关。Rs70950385(AG>；CA)变异被预测为为miR-1275创建一个microRNA结合位点，与正常代谢者(AG/AG vs.CA/CA[p<；0.05])中的CYP2B6活性降低33%相关。体外荧光素酶分析证实，当用miR-1275处理时，变异等位基因上的CA产生了一个microRNA结合位点，导致活性比AG等位基因降低11.3%(p=0.0035)。我们的结果表明，3‘非编码区变异导致了CYP2B6活性的变化。
CYP2B6*6 and CYP2B6*18 are the most clinically important variants causing reduced CYP2B6 protein expression and activity. However, these variants do not account for all variability in CYP2B6 activity. Emerging evidence has shown that genetic variants in the 3′UTR may explain variable drug response by altering microRNA regulation. Five 3′UTR variants were associated with significantly altered efavirenz AUC0-48 (8-OH-EFV/EFV) ratios in healthy human volunteers. The rs70950385 (AG>CA) variant, predicted to create a microRNA binding site for miR-1275, was associated with 33% decreased CYP2B6 activity among normal metabolizers (AG/AG vs. CA/CA [p<0.05]). In vitro luciferase assays were used to confirm that the CA on the variant allele created a microRNA binding site causing a 11.3% decrease in activity compared to the AG allele when treated with miR-1275 (p=0.0035). Our results show that a 3′UTR variant contributes to variability in CYP2B6 activity.
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影响因子：
44.1
作者：
Shi, YY;He, L
通讯作者：
He, L
影响因子：
8.8
作者：
Kharasch ED;Regina KJ;Blood J;Friedel C
通讯作者：
Friedel C
影响因子：
2.6
作者：
Nakajima, Miki;Komagata, Sayaka;Minami, Hironobu
通讯作者：
Minami, Hironobu
DOI：
10.1038/tpj.2013.17
发表时间：
2014-04
期刊：
The pharmacogenomics journal
影响因子：
--
作者：
Michaud V;Kreutz Y;Skaar T;Ogburn E;Thong N;Flockhart DA;Desta Z
通讯作者：
Desta Z
影响因子：
3.4
作者：
Jiang, Fen;Desta, Zeruesenay;Shin, Jae-Gook
通讯作者：
Shin, Jae-Gook