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

Abstract
Figure/Table
References (24)
Related Citation (4)

Download: PDF (792 KB) HTML (1 KB)
Export: BibTeX | EndNote (RIS)

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

	Service

	E-mail this article
	Add to my bookshelf
	Add to citation manager
	E-mail Alert
	RSS
	Articles by authors

Cite this article:

URL:

https://www.dangdaiyiyao.com/EN/ OR https://www.dangdaiyiyao.com/EN/Y2022/V29/I27/20

[1]	Senter PD，Beam KS，Mixan B，et al.Identification and activities of human carboxylesterases for the activation of CPT-11，a clinically approved anticancer drug[J].Bioconjug Chem，2001，12（6）：1074-1080.
[2]	Bijak M.Silybin，a Major Bioactive Component of Milk Thistle（Silybum marianum L.Gaernt.）-Chemistry，Bioavailability，and Metabolism[J].Molecules，2017，22（11）：1942.
[3]	Wang Z，Wang XY，Wang Z，et al.Prediction of Drug-Drug Interaction Between Dabrafenib and Irinotecan via UGT1A1-Mediated Glucuronidation[J].Eur J Drug Metab Pharmacokinet，2022，47（3）：353-361.
[4]	Wang Z，Wang X，Wang Z，et al.In vitro inhibition of human UDP-glucuronosyltransferase（UGT）1A1 by osimertinib，and prediction of in vivo drug-drug interactions[J].Toxicol Lett，2021，348：10-17.
[5]	国家药典委员会.中华人民共和国药典[M].北京：中国医药科技出版社，2020：355.
[6]	李时珍.本草纲目[M].北京：人民卫生出版社，1982：762.
[7]	Wang A，Fang S，Zhong L，et al.Shikonin，a promising therapeutic drug for osteoarthritis that acts via autophagy activation[J].Int Immunopharmacol，2022，106：108563.
[8]	Chen Y，Si L，Zhang J，et al.Uncovering the antitumor effects and mechanisms of Shikonin against colon cancer on comprehensive analysis[J].Phytomedicine，2021，82：153460.
[9]	Guo C，He J，Song X，et al.Pharmacological properties and derivatives of shikonin-A review in recent years[J].Pharmacol Res，2019，149：104463.
[10]	Sun Q，Gong T，Liu M，et al.Shikonin，a naphthalene ingredient：Therapeutic actions，pharmacokinetics，toxicology，clinical trials and pharmaceutical researches[J].Phytomedicine，2022，94：153805.
[11]	Lan T，Fang P，Ye X，et al.Evaluation of herb-drug interaction of ambrisentan with shikonin based on UPLC-MS/MS[J].Pharm Biol，2021，59（1）：1133-1138.
[12]	Huang MJ，Lin YC，Liu K，et al.Effects of variation status and enzyme activity for UDP-glucuronosyltransferase 1A1 gene on neonatal hyperbilirubinemia[J].Pediatr Neonatol，2020，61（5）：506-512.
[13]	Hulshof EC，de With M，de Man FM，et al.UGT1A1 genotype-guided dosing of irinotecan：A prospective safety and cost analysis in poor metaboliser patients[J].Eur J Cancer，2022，162：148-157.
[14]	Takano M，Sugiyama T.UGT1A1 polymorphisms in cancer：impact on irinotecan treatment[J].Pharmgenomics Pers Med，2017，10：61-68.
[15]	Hikino K，Ozeki T，Koido M，et al.Comparison of effects of UGT1A16 and UGT1A128 on irinotecan-induced adverse reactions in the Japanese population：analysis of the Biobank Japan Project[J].J Hum Genet，2019，64（12）：1195-1202.
[16]	Chen X，Liu L，Guo Z，et al.UGT1A1 polymorphisms with irinotecan-induced toxicities and treatment outcome in Asians with Lung Cancer：a meta-analysis[J].Cancer Chemother Pharmacol，2017，79（6）：1109-1117.
[17]	de Man FM，Goey AKL，van Schaik RHN，et al.Individualization of Irinotecan Treatment：A Review of Pharmacokinetics，Pharmacodynamics，and Pharmacogenetics[J].Clin Pharmacokinet，2018，57（10）：1229-1254.
[18]	Liu D，Zhang L，Duan LX，et al.Potential of herb-drug/herb interactions between substrates and inhibitors of UGTs derived from herbal medicines[J].Pharmacol Res，2019，150：104510.
[19]	王晓飞，马超，龚芬芬，等.恶性肿瘤患者UGT1A1 基因多态性与伊立替康所致严重不良反应的关系[J].中华肿瘤杂志，2018，40（8）：594-599.
[20]	Cheng Y，Tang S，Chen A，et al.Evaluation of the inhibition risk of shikonin on human and rat UDP-glucuronosyltransferases（UGT）through the cocktail approach[J].Toxicol Lett，2019，312：214-221.
[21]	Zou L，Harkey MR，Henderson GL.Effects of herbal components on cDNA-expressed cytochrome P450 enzyme catalytic activity[J].Life Sci，2002，71（13）：1579-1589.
[22]	Yang Y，Zhou M，Hu M，et al.UGT1A16 and UGT1A128 polymorphisms are correlated with irinotecan-induced toxicity：A meta-analysis[J].Asia Pac J Clin Oncol，2018，14（5）：e479-e489.
[23]	Han JY，Lim HS，Park YH，et al.Integrated pharmacogenetic prediction of irinotecan pharmacokinetics and toxicity in patients with advanced non-small cell lung cancer[J].Lung Cancer，2009，63（1）：115-120.
[24]	Satoh T，Ura T，Yamada Y，et al.Genotype-directed，dosefindingstudyofirinotecanincancerpatientswithUGT1A128 and/or UGT1A16 polymorphisms[J].Cancer Sci，2011，102（10）：1868-1873.