Discovery of Novel Reductive Elimination Pathway for 10-Hydroxywarfarin.
Discovery of Novel Reductive Elimination Pathway for 10-Hydroxywarfarin.
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DOI：
10.3389/fphar.2021.805133
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发表时间：
2021
影响因子：
5.6
通讯作者：
Miller GP
中科院分区：
文献类型：
--
作者：
Pouncey DL;Barnette DA;Sinnott RW;Phillips SJ;Flynn NR;Hendrickson HP;Swamidass SJ;Miller GP
香豆素（R/S-华法林）抗凝治疗对于预防血栓形成非常有效；然而，个体间反应的显着差异可能导致剂量过高或过低，分别导致不良出血事件或无效治疗。药物和代谢物的药理活性形式的水平取决于代谢途径的多样性。细胞色素 P450 在将 R- 和 S-华法林氧化为 6-、7-、8-、10- 和 4'-羟基华法林方面发挥着主要作用，并且华法林醇通过涉及 C11 位还原的次要代谢途径形成。我们假设，由于与华法林的结构相似，羟基华法林会被还原，可能会影响其药理活性和消除。我们模拟了还原反应，并用人肝细胞质进行了实验稳态反应，将 rac-6-、7-、8-、4'-羟基华法林和 10-羟基华法林异构体转化为相应的醇。该模型正确预测了 10-羟基华法林比华法林更有效的减少，但没有预测剩余羟基华法林的顺序。实验研究没有表明外消旋羟基华法林或 10-羟基华法林还原为醇 1 和 2 的任何明显趋势。集体发现表明羟基的位置显着影响羟基华法林之间的还原选择性以及所得代谢物的特异性。根据对 R- 和 S-7-羟基华法林的研究，我们预测所有羟基华法林还原对 R 底物具有对映选择性，对 S 醇代谢物具有对映特异性。 CBR1 和较小程度上的 AKR1C3 还原酶负责这些反应。由于反应效率低下，只有 10-羟基华法林的还原可能对代谢物的清除很重要。考虑到 10-羟基华法林的抗凝活性和抑制 S-华法林代谢的能力，该途径也可能具有临床相关性。
Coumadin (R/S-warfarin) anticoagulant therapy is highly efficacious in preventing the formation of blood clots; however, significant inter-individual variations in response risks over or under dosing resulting in adverse bleeding events or ineffective therapy, respectively. Levels of pharmacologically active forms of the drug and metabolites depend on a diversity of metabolic pathways. Cytochromes P450 play a major role in oxidizing R- and S-warfarin to 6-, 7-, 8-, 10-, and 4′-hydroxywarfarin, and warfarin alcohols form through a minor metabolic pathway involving reduction at the C11 position. We hypothesized that due to structural similarities with warfarin, hydroxywarfarins undergo reduction, possibly impacting their pharmacological activity and elimination. We modeled reduction reactions and carried out experimental steady-state reactions with human liver cytosol for conversion of rac-6-, 7-, 8-, 4′-hydroxywarfarin and 10-hydroxywarfarin isomers to the corresponding alcohols. The modeling correctly predicted the more efficient reduction of 10-hydroxywarfarin over warfarin but not the order of the remaining hydroxywarfarins. Experimental studies did not indicate any clear trends in the reduction for rac-hydroxywarfarins or 10-hydroxywarfarin into alcohol 1 and 2. The collective findings indicated the location of the hydroxyl group significantly impacted reduction selectivity among the hydroxywarfarins, as well as the specificity for the resulting metabolites. Based on studies with R- and S-7-hydroxywarfarin, we predicted that all hydroxywarfarin reductions are enantioselective toward R substrates and enantiospecific for S alcohol metabolites. CBR1 and to a lesser extent AKR1C3 reductases are responsible for those reactions. Due to the inefficiency of reactions, only reduction of 10-hydroxywarfarin is likely to be important in clearance of the metabolite. This pathway for 10-hydroxywarfarin may have clinical relevance as well given its anticoagulant activity and capacity to inhibit S-warfarin metabolism.
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影响因子：
0.4
作者：
Kumar, Dhakchinamoorthi Krishna;Shewade, Deepak Gopal;Adithan, Chandrasekaran
通讯作者：
Adithan, Chandrasekaran
影响因子：
5.8
作者：
Malatkova, Petra;Sokolova, Simona;Wsol, Vladimir
通讯作者：
Wsol, Vladimir
影响因子：
3.9
作者：
Kassner, Nina;Huse, Klaus;Wojnowski, Leszek
通讯作者：
Wojnowski, Leszek
DOI：
10.1016/j.jchromb.2013.11.014
发表时间：
2014-01-01
影响因子：
3
作者：
Alshogran, Osama Y.;Ocque, Andrew J.;Nolin, Thomas D.
通讯作者：
Nolin, Thomas D.
影响因子：
1.1
作者：
Pouncey, Dakota L.;Hartman, Jessica H.;Miller, Grover P.
通讯作者：
Miller, Grover P.