Herb-drug interaction prediction based on the high specific inhibition of andrographolide derivatives towards UDP-glucuronosyltransferase (UGT) 2B7.
Herb-drug interaction prediction based on the high specific inhibition of andrographolide derivatives towards UDP-glucuronosyltransferase (UGT) 2B7.
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DOI：
10.1016/j.taap.2014.02.021
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发表时间：
2014-05-15
影响因子：
3.8
通讯作者：
Fang ZZ
中科院分区：
文献类型：
--
作者：
Ma HY;Sun DX;Cao YF;Ai CZ;Qu YQ;Hu CM;Jiang C;Dong PP;Sun XY;Hong M;Tanaka N;Gonzalez FJ;Ma XC;Fang ZZ
中药相互作用严重限制了中药的临床应用，中药成分对重要药物代谢酶的抑制作用被认为是其中一个重要原因。本研究旨在研究穿心莲内酯衍生物对最重要的II相DME之一UDP-葡萄糖醛酸转移酶（UGT）的抑制潜力。采用重组UGT异构体（UGT 1A 4除外）催化的4-甲基伞形酮（4-MU）葡萄糖醛酸化反应和UGT 1A 4催化的三氟拉嗪（TFP）葡萄糖醛酸化反应，首次筛选穿心莲内酯衍生物的抑制潜力。观察到穿心莲内酯衍生物对UGT 2B 7的高特异性抑制。测定了对UGT 2B 7具有较强抑制能力的化合物的抑制类型和抑制参数（Ki），并利用人肝微粒体（HLM）催化的齐多夫定（AZT）葡萄糖醛酸化探针反应进一步证实了抑制行为。结合抑制参数（Ki）和穿琥宁和脱水穿琥宁的体内浓度，预测潜在的体内抑制幅度。此外，体外抑制数据和计算建模结果都为穿心莲内酯衍生物作为UGT 2B 7选择性抑制剂的修饰提供了重要信息。综上所述，从本研究中获得的数据表明，穿心莲和药物之间的潜在的草药相互作用主要经历UGT 2B 7催化代谢消除，和穿心莲内酯衍生物作为UGT 2B 7的选择性抑制剂的潜在候选人。
Herb–drug interaction strongly limits the clinical application of herbs and drugs, and the inhibition of herbal components towards important drug-metabolizing enzymes (DMEs) has been regarded as one of the most important reasons. The present study aims to investigate the inhibition potential of andrographolide derivatives towards one of the most important phase II DMEs UDP-glucuronosyltransferases (UGTs). Recombinant UGT isoforms (except UGT1A4)-catalyzed 4-methylumbelliferone (4-MU) glucuronidation reaction and UGT1A4-catalyzed trifluoperazine (TFP) glucuronidation were employed to firstly screen the andrographolide derivatives’ inhibition potential. High specific inhibition of andrographolide derivatives towards UGT2B7 was observed. The inhibition type and parameters (Ki) were determined for the compounds exhibiting strong inhibition capability towards UGT2B7, and human liver microsome (HLMs)-catalyzed zidovudine (AZT) glucuronidation probe reaction was used to furtherly confirm the inhibition behavior. In combination of inhibition parameters (Ki) and in vivo concentration of andrographolide and dehydroandrographolide, the potential in vivo inhibition magnitude was predicted. Additionally, both the in vitro inhibition data and computational modeling results provide important information for the modification of andrographolide derivatives as selective inhibitors of UGT2B7. Taken together, data obtained from the present study indicated the potential herb–drug interaction between Andrographis paniculata and the drugs mainly undergoing UGT2B7-catalyzed metabolic elimination, and the andrographolide derivatives as potential candidates for the selective inhibitors of UGT2B7.
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影响因子：
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