Metabolic Activation of Retrorsine may Disrupt Bile Acid Homeostasis in Mice through the Nrf2 Pathway
文献类型：期刊论文
| 作者 | Pang, Xiaoyan1; Tang, Chongzhuang1; Cao, Peng2; Zhou, Lei1; Chen, Xiaoyan1
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| 刊名 | CURRENT DRUG METABOLISM
 |
| 出版日期 | 2021 |
| 卷号 | 22期号:11页码:870-881 |
| 关键词 | Retrorsine bile acid oxidative stress reactive metabolite transporter Nrf2 |
| ISSN号 | 1389-2002 |
| DOI | 10.2174/1389200222666210427124332 |
| 通讯作者 | Chen, Xiaoyan(xychen@simm.ac.cn) |
| 英文摘要 | Background: The hepatotoxic pyrrolizidine alkaloids (PAs) were reported to increase bile acid (BA) levels in the rat. However, it is still unclear whether the production of highly reactive dehydropyrrolizidine through CYP450s is directly relevant to BA changes. Objective: To further explore the mechanism by which metabolic activation of PAs induced BA changes, the effect of impaired or enhanced metabolic activation on the BA profiling and BA-related synthesis and to investigate transport genes, and explore the involvement of the Nrf2 pathway. Methods: Blood and liver samples were collected after intragastrical administration of 35 mg/kg retrorsine or saline for seven days in wild-type (WT) and Nrf2 KO mice. CYP450 inhibitor, 1-aminobenzotriazole (ABT), or gammaglutamylcysteine synthetase inhibitor, L-buthionine-sulfoximine (BSO) were employed in WT mice. Retrorsineinduced hepatotoxicity was evaluated by a biochemical method and H&E staining method. Serum BAs were quantified by high-performance liquid chromatography/triple quadrupole mass spectrometry. Blood pyrrole-protein adducts were semi quantified by high-performance liquid chromatography/quadrupole time-of-flight mass spectrometry. The gene and protein expression of BA-related transporters and enzymes in the liver were measured by a quantitative real-time PCR method and western blotting method. Results: The BA concentrations in serum were increased in the retrorsine-treated WT mice, along with the upregulation of BA transporters, Ost/3, Mrp3, Mrp4, and Mrp2. When ABT was co-administered, the altered BA levels and Mrp4 mRNA and protein levels were reversed, accompanied by a 50% reduction of 6,7-dihydro-7-hydroxy-1hydroxymethyl-5H-pyrrolizine (DHP) formation. When BSO was co-administered, serum BAs were not further increased, but Ost/3, Mrp3, Mrp4 mRNA, and Mrp4 protein levels continuously increased. The induction of Mrp4 by retrorsine among the tested BA transporters was the only one that was abolished or enhanced in the presence of ABT or BSO. The Nrf2 protein levels in the nucleus increased in the retrorsine-treated WT mice, which were remarkably repressed by co-administration of ABT and enhanced by co-administration of BSO. In Nrf2 KO mice receiving retrorsine, the bile acids and the mRNA and protein levels of Mrp2, Mrp3, Mrp4, and Ost beta were hardly changed, indicating the direct role of Nrf2 in retrorsine-induced BA changes in WT mice. Conclusion: The activation of Nrf2 translocation by forming the reactive metabolite of PAs induced the expressions of BA transporters and changed serum BA levels. Mrp4 was a sensitive biomarker for the perturbation of redox status caused by the formation of dehydropyrrolizidine. |
| WOS关键词 | PYRROLIZIDINE ALKALOIDS ; DRUG-METABOLISM ; ACUTE TOXICITY ; LIVER ; GLUTATHIONE ; PROTECTS ; STRESS ; INJURY ; 4-AMINOBIPHENYL ; HEPATOTOXICITY |
| 资助项目 | National Natural Science Foundation of China[81503153] ; Natural Science Foundation of Shanghai, China[15ZR1447700] |
| WOS研究方向 | Biochemistry & Molecular Biology ; Pharmacology & Pharmacy |
| 语种 | 英语 |
| WOS记录号 | WOS:000745114300004 |
| 出版者 | BENTHAM SCIENCE PUBL LTD |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/300568]  |
| 专题 | 中国科学院上海药物研究所 |
| 通讯作者 | Chen, Xiaoyan |
| 作者单位 | 1.Chinese Acad Sci, Shanghai Inst Mat Med, 501 Haike Rd, Shanghai 201203, Peoples R China 2.Nanjing Univ Chinese Med, Affiliated Hosp Integrated Tradit Chinese & Weste, Nanjing 210028, Peoples R China |
| 推荐引用方式 GB/T 7714 | Pang, Xiaoyan,Tang, Chongzhuang,Cao, Peng,et al. Metabolic Activation of Retrorsine may Disrupt Bile Acid Homeostasis in Mice through the Nrf2 Pathway[J]. CURRENT DRUG METABOLISM,2021,22(11):870-881. |
| APA | Pang, Xiaoyan,Tang, Chongzhuang,Cao, Peng,Zhou, Lei,&Chen, Xiaoyan.(2021).Metabolic Activation of Retrorsine may Disrupt Bile Acid Homeostasis in Mice through the Nrf2 Pathway.CURRENT DRUG METABOLISM,22(11),870-881. |
| MLA | Pang, Xiaoyan,et al."Metabolic Activation of Retrorsine may Disrupt Bile Acid Homeostasis in Mice through the Nrf2 Pathway".CURRENT DRUG METABOLISM 22.11(2021):870-881. |
入库方式： OAI收割
来源：上海药物研究所
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