Probing Ligand Structure-Activity Relationships in Pregnane X Receptor (PXR): Efavirenz and 8-Hydroxyefavirenz Exhibit Divergence in Activation.
Probing Ligand Structure-Activity Relationships in Pregnane X Receptor (PXR): Efavirenz and 8-Hydroxyefavirenz Exhibit Divergence in Activation.
复制标题
DOI：
10.1002/cmdc.201700730
复制
发表时间：
2018-04-06
期刊：
影响因子：
3.4
通讯作者：
Bumpus NN
中科院分区：
文献类型：
--
作者：
Narayanan B;Lade JM;Heck CJS;Dietz KD;Wade H;Bumpus NN
依法韦仑（EFV）是一种抗逆转录病毒药物，在临床上可通过激活胞苷烷X受体（PXR）与联合用药相互作用，并被细胞色素P450广泛代谢。我们测试了其主要代谢产物8-羟基EFV（8-OHEFV）是否可以激活PXR，并可能导致EFV引起的PXR介导的药物相互作用。荧光素酶报告基因分析显示，尽管8-OHEFV与EFV的区别仅在于氧原子，但8-OHEFV不激活PXR。证实了这一点，EFV处理72小时提高了PXR靶基因Cyp 3a 11的mRNA丰度，在从PXR人源化小鼠分离的原代肝细胞中约28倍，而8-OHEFV处理未导致Cyp 3a 11 mRNA水平的变化。基于FRET的竞争性结合试验和等温量热法表明，即使缺乏激活PXR的能力，8-OHEFV对PXR的亲和力（IC 50 12.1 µM; KD 7.9 µM）与EFV（IC 50 18.7 µM; KD 12.5 µM）几乎相同。16种EFV类似物的使用表明，EFV结构在8位以外的其他谨慎变化是耐受良好的。分子对接模拟暗示了8-OHEFV结合模式，这可能是EFV在PXR激活中的分歧的基础。依法韦仑在临床上与联合给药的药物通过激活胞苷烷X受体相互作用，并被细胞色素P450广泛代谢。其主要代谢产物8-羟基EFV（8-OHEFV）在长期使用EFV后以接近1：1的比例与EFV循环。我们确定8-OHEFV不激活PXR，因此不太可能促成归因于EFV的PXR介导的药物-药物相互作用。虽然它缺乏激活PXR的能力，但8-OHEFV似乎以与EFV几乎相同的亲和力结合PXR。分子对接表明，8-OHEFV表现出与EFV不同的结合模式，这可能是PXR激活差异的基础。
Efavirenz (EFV), an antiretroviral that interacts clinically with co-administered drugs via activation of the pregnane X receptor (PXR), is extensively metabolized by the cytochromes P450. We tested whether its primary metabolite, 8-hydroxyEFV (8-OHEFV) can activate PXR and potentially contribute to PXR-mediated drug-drug interactions attributed to EFV. Luciferase reporter assays revealed that despite only differing from EFV by an oxygen atom, 8-OHEFV did not activate PXR. Corroborating this, treatment with EFV for 72 h elevated the mRNA abundance of the PXR target gene, Cyp3a11, an approximate 28-fold in primary hepatocytes isolated from PXR-humanized mice while treatment with 8-OHEFV did not result in a change in Cyp3a11 mRNA levels. FRET-based competitive binding assays and isothermal calorimetry demonstrated that even with the lack of ability to activate PXR, 8-OHEFV displays an affinity for PXR (IC50 12.1 µM; KD 7.9 µM) nearly identical to that of EFV (IC50 18.7 µM; KD 12.5 µM). The use of 16 EFV analogs suggest that other discreet changes to the EFV structure beyond the 8-position are well-tolerated. Molecular docking simulations implicate an 8-OHEFV binding mode that may underlie its divergence in PXR activation from EFV. Efavirenz interacts clinically with co-administered drugs via activation of the pregnane X receptor and is extensively metabolized by the cytochromes P450. Its primary metabolite, 8-hydroxyEFV (8-OHEFV), circulates in a near 1:1 ratio with EFV following chronic EFV use. We determined that 8-OHEFV does not activate PXR and thereby does not likely contribute to PXR-mediated drug-drug interactions attributed to EFV. Although it lacks the ability to activate PXR, 8-OHEFV appears to bind PXR with an affinity nearly identical to EFV. Molecular docking indicates that 8-OHEFV exhibits a binding mode distinct from EFV, which may underlie the divergence in PXR activation.
登录
查看更多内容
影响因子：
16.6
作者：
Delfosse V;Dendele B;Huet T;Grimaldi M;Boulahtouf A;Gerbal-Chaloin S;Beucher B;Roecklin D;Muller C;Rahmani R;Cavaillès V;Daujat-Chavanieu M;Vivat V;Pascussi JM;Balaguer P;Bourguet W
通讯作者：
Bourguet W
影响因子：
3.5
作者：
Ratajewski, Marcin;Grzelak, Izabela;Dastych, Jaroslaw
通讯作者：
Dastych, Jaroslaw
影响因子：
2.9
作者：
Krieger, E;Darden, T;Vriend, G
通讯作者：
Vriend, G
DOI：
10.1124/jpet.106.112136
发表时间：
2007-01-01
影响因子：
3.5
作者：
Faucette, Stephanie R.;Zhang, Tong-Cun;Wang, Hongbing
通讯作者：
Wang, Hongbing
影响因子：
3
作者：
Morris, Garrett M.;Huey, Ruth;Lindstrom, William;Sanner, Michel F.;Belew, Richard K.;Goodsell, David S.;Olson, Arthur J.
通讯作者：
Olson, Arthur J.