Effects of <italic style="font-style: italic">Gelsemium elegans</italic> Combined with <italic style="font-style: italic">Mussaenda pubescens </italic>on Transporter BCRP and Drug-metabolizing Enzyme CYP3A11

Cui-ping ZHU; Han-yun GAO; Qian-qian ZHAO; Xiang-xiang LIU; Mei-xia HUANG; Ying-hao WANG

doi:10.13422/j.cnki.syfjx.20220192

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Effects of Gelsemium elegans Combined with Mussaenda pubescens on Transporter BCRP and Drug-metabolizing Enzyme CYP3A11

更新时间：2022-01-04

- Effects of Gelsemium elegans Combined with Mussaenda pubescens on Transporter BCRP and Drug-metabolizing Enzyme CYP3A11
- Chinese Journal of Experimental Traditional Medical Formulae Vol. 28, Issue 1, Pages: 58-64(2022)
- 作者机构：
  
  福建中医药大学，福州 350122
- 作者简介：
- 基金信息：
- DOI：10.13422/j.cnki.syfjx.20220192
  CLC： R22;R242;R285.5;R2-031
- Received：29 March 2021，
  
  Published Online：08 November 2021，
  
  Published：05 January 2022
- 稿件说明：
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朱翠萍,高汉云,赵茜茜等.钩吻配伍玉叶金花对外排转运蛋白BCRP和药物代谢酶CYP3A11的影响[J].中国实验方剂学杂志,2022,28(01):58-64.

ZHU Cui-ping,GAO Han-yun,ZHAO Qian-qian,et al.Effects of Gelsemium elegans Combined with Mussaenda pubescens on Transporter BCRP and Drug-metabolizing Enzyme CYP3A11[J].Chinese Journal of Experimental Traditional Medical Formulae,2022,28(01):58-64.
朱翠萍,高汉云,赵茜茜等.钩吻配伍玉叶金花对外排转运蛋白BCRP和药物代谢酶CYP3A11的影响[J].中国实验方剂学杂志,2022,28(01):58-64. DOI： 10.13422/j.cnki.syfjx.20220192.

ZHU Cui-ping,GAO Han-yun,ZHAO Qian-qian,et al.Effects of Gelsemium elegans Combined with Mussaenda pubescens on Transporter BCRP and Drug-metabolizing Enzyme CYP3A11[J].Chinese Journal of Experimental Traditional Medical Formulae,2022,28(01):58-64. DOI： 10.13422/j.cnki.syfjx.20220192.

摘要

目的

钩吻配伍玉叶金花对外排转运蛋白乳腺癌耐药蛋白（BCRP）和细胞色素P450 3A11（CYP3A11）的影响，探讨其配伍减毒的机制；同时添加核受体激活剂干预探讨核受体是否在该过程中有调节作用。

方法

将C57BL/6小鼠分为空白组，钩吻组（GE组，0.25 g·kg

-1

），钩吻配伍玉叶金花组（GE+MP组，0.25 g·kg

-1

+10 g·kg

-1

），钩吻+孕烷X受体（PXR）激活剂（利福平）组（GE+Rif组，0.25 g·kg

-1

+50 mg·kg

-1

），配伍+利福平组（GE+MP+Rif组，0.25 g·kg

-1

+10 g·kg

-1

+50 mg·kg

-1

），钩吻+组成型雄甾烷受体（CAR）激活剂｛1，4-双［2-（3，5-二氯吡啶氧）］苯，TCPOBOP｝组（GE+TCP组，0.25 g·kg

-1

+0.5 mg·kg

-1

），配伍+CAR激活剂组（GE+MP+TCP组，0.25 g·kg

-1

+10 g·kg

-1

+0.5 mg·kg

-1

）。连续给药14 d，末次给药1 h后脱颈处死小鼠，取肝组织。左肝组织采用苏木素-伊红（HE）染色观察其病理学变化；右肝组织采用实时荧光定量聚合酶链式反应（Real-time PCR），蛋白免疫印迹法（Western blot）对其进行mRNA及蛋白水平的检测，检测其对BCRP，CYP3A11基因和蛋白的影响。

结果

GE+Rif组小鼠存活率25%，存活率最低，GE组存活率40%，GE+MP组存活率为80%，其他组均存活未见死亡。GE组小鼠肝脏细胞出现明显病变，与GE组比较，GE+MP组肝细胞病理状态都有所缓解；GE+Rif组小鼠肝脏细胞病理状态严重，与GE+Rif组比较，GE+MP+Rif组小鼠肝脏细胞肝细胞病变有所缓解；GE+TCP组小鼠肝脏出现轻微病变，GE+MP+TCP组小鼠肝脏细胞病变不明显；与GE+MP组比较，GE+MP+TCP组病变程度有轻微缓解但差异不大。与空白组比较，GE组BCRP蛋白及mRNA表达明显下调（

0.05，

0.01）；GE组CYP3A11蛋白表达显著下调（

0.01），mRNA表达有下调趋势但差异无统计学意义。与GE组比较，GE+MP组BCRP蛋白及mRNA表达均明显上调（

0.05，

0.01）；CYP3A11蛋白及mRNA表达有上调趋势，但差异无统计学意义。与GE组比较，GE+Rif组BCRP蛋白表达明显下调（

0.05）；与GE+MP组比较，GE+MP+Rif组BCRP蛋白及mRNA表达明显下调（

0.05，

0.01）；PXR激活剂利福平在钩吻配伍前后均对BCRP产生调节。与GE组比较，GE+TCP组CYP3A11蛋白和mRNA表达明显上调（

0.05，

0.01）；与GE+MP组比较，GE+MP+TCP组CYP3A11蛋白和mRNA表达明显上调（

0.05，

0.01）；CAR激活剂TCPOBOP在钩吻配伍前后对CYP3A11也存在调节作用。

结论

钩吻配伍玉叶金花毒性降低与外排转运蛋白BCRP和药物代谢酶CYP3A11密切相关。

Abstract

Objective

To explore the effect of

Gelsemium elegans

combined with

Mussaenda pubescens

on efflux transporter breast cancer resistance protein （BCRP） and cytochrome P450 3A11 （CYP3A11） and their attenuation mechanism， and to investigate whether the nuclear receptors were involved in such regulation by intervening it with nuclear receptor activators.

Method

C57BL/6 mice were divided into the blank group，

G. elegans

（GE， 0.25 g·kg

-1

）group， GE +

M. pubescens

（MP）（0.25 g·kg

-1

+10 g·kg

-1

） group， GE

+ pregnane X receptor （PXR） activator （rifampicin）（GE + Rif，0.25 g·kg

-1

+50 mg·kg

-1

） group， GE + MP + Rif （0.25 g·kg

-1

+10 g·kg

-1

+50 mg·kg

-1

） group， GE + constitutive androstane receptor （CAR） activator （1，4-Bis ［2-（3，5-Dichloropyridyloxy）］ benzene， TCPOBOP）（GE + TCP， 0.25 g·kg

-1

+0.5 mg·kg

-1

） group， and GE + MP + TCP （0.25 g·kg

-1

+10 g·kg

-1

+0.5 mg·kg

-1

） group. The medication lasted for 14 successive days. One hour after the last administration， the mice were sacrificed by cervical dislocation and the liver tissue was harvested. The left liver tissue was stained with hematoxylin- eosin （HE） for observing the pathological changes. The right liver tissue was used for BCRP and CYP3A11 mRNA and protein expression detection by real-time fluorescence quantitative polymerase chain reaction （Real-time PCR） and Western blot.

Result

The survival rates of mice in the GE + Rif group， GE group， and GE + MP group were 25% （the lowest）， 40%， and 80%， respectively， and no death was observed in the other groups. Compared with the obvious lesions in the liver cells of the

GE group， the pathological changes in liver cells of the GE + MP group were alleviated， while those in the GE + Rif group were worsened. Compared with the GE + Rif group， the GE + MP + Rif group exhibited relieved pathological changes in liver cells. Both the GE + TCP group and the GE + MP + TCP group showed mild liver lesions. The comparison with the GE + MP group revealed that the pathological changes in the GE + MP + TCP group were slightly relieved. Compared with the blank group， the expression of BCRP protein and mRNA in GE group were significantly decreased （

0.05，

0.01）.The expression of CYP3A11 protein in GE group were significantly decreased （

0.01）. Compared with the GE group， the GE + MP group displayed remarkably up-regulated BCRP protein and mRNA expression （

0.05，

0.01） and CYP3A11 protein expression （

0.05）， but slightly up-regulated CYP3A11 mRNA expression. Compared with the GE group， the GE + Rif group exhibited down-regulated BCRP protein expression （

0.05）. The protein and mRNA expression levels of BCRP were lower in the GE + MP + Rif group than in the GE + MP group （

0.05，

0.01）. The PXR activator rifampicin regulated BCRP before and after the combination of

G. elegans

with

M. pubescens

. The CYP3A11 protein and mRNA expression levels in the GE + TCP group were higher than those in the GE group （

0.05，

0.01）. Compared with the GE + MP group， the GE + MP + TCP group showed up-regulated CYP3A11 protein and mRNA expression （

0.05，

0.01）. CAR activator TCPOBOP also had a regulatory effect on CYP3A11 before and after the compatibility of

G. elegans

with

M. pubescens

Conclusion

The attenuated toxin after the combination of

G. elegans

with

M. pubescens

is closely related to the efflux transporter BCRP and the drug-metabolizing enzyme CYP3A11.

关键词

Keywords

references

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Ya-ting ZHAO

Shu-peng WU

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Meng ZHAO

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Shanxi Normal University

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⁰

Effects of Gelsemium elegans Combined with Mussaenda pubescens on Transporter BCRP and Drug-metabolizing Enzyme CYP3A11

DOI：10.13422/j.cnki.syfjx.20220192

摘要

Abstract

关键词

Keywords

references