紫草素对UGT1A1*1和UGT1A1*6催化SN-38葡萄糖醛酸化的抑制作用研究

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摘要目的比较紫草素对野生型UDP-葡萄糖苷酸转移酶1A1（UGT1A1*1）及其在亚洲人群中常见的单核苷酸突变UGT1A1*6 催化SN-38 葡萄糖醛酸化抑制作用的差异。方法采用超高效液相色谱-串联质谱（UPLC-MS/MS）法检测SN-38 代谢产物SN-38 葡萄糖醛酸酯（SN-38G）的生成速率，利用酶剩余活性的变化评价紫草素对UGT1A1*1 和UGT1A1*6 催化SN-38 代谢的抑制作用。非线性回归计算获得紫草素在UGT1A1*1 和UGT1A1*6体系中对SN-38G 的半抑制浓度（IC50）。结果紫草素（1、10、100 μmol/L）可使UGT1A1*1 和UGT1A1*6 催化SN-38 葡萄糖醛酸化的反应速率均低于对照组（未加紫草素），差异有统计学意义（P<0.05）。其对UGT1A1*1 和UGT1A1*6 活性的IC50 分别为4.357 μmol/L 和7.353 μmol/L。结论紫草素可能通过抑制UGT1A1，进而降低前药伊立替康活性形式SN-38 的代谢清除，从而造成草药-药物相互作用。因此，临床用药中应避免紫草素制剂与伊立替康的联合用药，以避免SN-38 在体内积累引发临床不良发应。

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关键词 ： SN-38, 紫草素, UGT1A*1, UGT1A1*6, 药物相互作用

Abstract：Objective To compare the inhibitory effects of shikonin on SN-38 glucuronidation catalyzed by wild-type UDP-glucuronosyltransferase 1A1 (UGT1A1*1) and its common single nucleotide variant UGT1A1*6 in Asian population. Methods The production rate of SN-38 glucuronides (SN-38G), the metabolite of SN-38, was detected by ultraperformance liquid chromatography tandem mass spectrometry (UPLC-MS/MS). The inhibitory effects of shikonin on the metabolism of SN-38 catalyzed by UGT1A1*1 and UGT1A1*6 were evaluated by the change of the residual activity of the enzymes. The half-maximal inhibitory concentration (IC50) of shikonin on SN-38G in UGT1A1*1 and UGT1A1*6 systems was calculated by nonlinear regression. Results The reaction rates of UGT1A1*1 and UGT1A1*6 catalyzed SN-38 glucuronidation by shikonin (1, 10, 100 μmol/L) were lower than those of the control group, with statistical significances (P<0.05). The IC50 of shikonin on UGT1A1*1 and UGT1A1*6 were 4.357 μmol/L and 7.353 μmol/L, respectively. Conclusion Shikonin may cause herbal drug interaction by inhibiting UGT1A1, and thereby reduce the metabolic clearance SN-38, which is the active form of the prodrug irinotecan. Thus, the combination of shikonin and irinotecan should be avoided in clinical practices to prevent the accumulation of SN-38 in the body and the consequent adverse reactions.

Key words： SN-38 Shikonin UGT1A1*1 UGT1A1*6 Drug interaction

基金资助:江苏省扬州市级计划社会发展项目（YZ2020084）

通讯作者: 李巍（1982-），女，辽宁开原人，博士，研究方向：药物代谢。

作者简介: 陈银楠（1996-），女，扬州大学医学院2020 级中药学专业在读硕士研究生，研究方向：药物代谢。

引用本文:

陈银楠；；刘勇；陈悦悦；李巍. 紫草素对UGT1A1*1和UGT1A1*6催化SN-38葡萄糖醛酸化的抑制作用研究[J]. 中国当代医药, 2022, 29(27): 20-24.
CHEN Yinnan； LIU Yong；CHEN Yueyue； LI Wei. Inhibitory effect of shikonin on SN -38 glucuronidation catalyzed by UGT1A1*1 and UGT1A1*6. 中国当代医药, 2022, 29(27): 20-24.

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https://www.dangdaiyiyao.com/CN/ 或 https://www.dangdaiyiyao.com/CN/Y2022/V29/I27/20

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