Metabolic Activation of Pyrrolizidine Alkaloids: Insights into the Structural and Enzymatic Basis
文献类型：期刊论文
| 作者 | Ruan, Jianqing1,2,3; Yang, Mengbi1,2,3; Fu, Peter4; Ye, Yang1,3,5 ; Lin, Ge1,2,3
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| 刊名 | CHEMICAL RESEARCH IN TOXICOLOGY
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| 出版日期 | 2014-06 |
| 卷号 | 27期号:6页码:1030-1039 |
| ISSN号 | 0893-228X |
| DOI | 10.1021/tx500071q |
| 文献子类 | Article |
| 英文摘要 | Pyrrolizidine alkaloids (PM) are natural toxins widely distributed in plants. The toxic potencies of different PM vary significantly. PM are mono- or diesters of necine acids with a necine base. On the basis of the necine bases, PM are classified into three types: retronecine-type, otonecine-type, and platynecine-type. Hepatotoxic PM contain an unsaturated necine base. PAs exert hepatotoxicity through metabolic activation by hepatic cytochromes P450s (CYPs) to generate reactive intermediates which form pyrrole protein adducts. These adducts provide a mechanism-based biomarker to assess PA toxicity. In the present study, metabolic activation of 12 PM from three structural types was investigated first in mice to demonstrate significant variations in hepatic metabolic activation of different PM. Subsequently, the structural and enzymatic factors affecting metabolic activation of these PM were further investigated by using human liver microsomes and recombinant human CYPs. Pyrrole protein adducts were detected in the liver and blood of mice and the in vitro systems treated with toxic retronecine-type and otonecine-type PM having unsaturated necine bases but not with a platynecine-type PA containing a saturated necine base. Retronecine-type PM produced more pyrrole protein adducts than otonecine-type PM with similar necine acids, demonstrating that the structure of necine base affected PA toxic potency. Among retronecine-type PM, open-ring diesters generated the highest amount of pyrrole protein adducts, followed by macrocyclic diesters, while monoesters produced the least. Only CYP3A4 and CYP3A5 activated otonecine-type PM, while all 10 CYPs studied showed the ability to activate retronecine-type PM. Moreover, the contribution of major CYPs involved also varied significantly among retronecine-type PM. In conclusion, our findings provide a scientific basis for predicting the toxicities of individual PM in biological systems based on PA structural features and on the pattern of expression and the selectivity of the CYP isoforms present. |
| WOS关键词 | DNA CROSS-LINKING ; RAT-LIVER ; CLIVORINE ; SENECIONINE ; TOXICITY ; TUMORIGENICITY ; HEPATOTOXICITY ; MICROSOMES ; ADDUCTS |
| 资助项目 | Research Grant Council of Hong Kong[471013] ; Research Grant Council of Hong Kong[469712] ; Chinese University of Hong Kong[4054047] |
| WOS研究方向 | Pharmacology & Pharmacy ; Chemistry ; Toxicology |
| 语种 | 英语 |
| WOS记录号 | WOS:000337557500013 |
| 出版者 | AMER CHEMICAL SOC |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/277047]  |
| 专题 | 天然药物化学研究室 中科院受体结构与功能重点实验室 新药研究国家重点实验室 |
| 通讯作者 | Lin, Ge |
| 作者单位 | 1.Chinese Univ Hong Kong, Hong Kong, Hong Kong, Peoples R China; 2.Chinese Univ Hong Kong, Sch Biomed Sci, Hong Kong, Hong Kong, Peoples R China; 3.Chinese Acad Sci, Joint Res Lab Promoting Globalizat Tradit Chinese, Hong Kong, Hong Kong, Peoples R China; 4.US FDA, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA; 5.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res & Nat Prod, Dept Chem, Shanghai 201203, Peoples R China |
| 推荐引用方式 GB/T 7714 | Ruan, Jianqing,Yang, Mengbi,Fu, Peter,et al. Metabolic Activation of Pyrrolizidine Alkaloids: Insights into the Structural and Enzymatic Basis[J]. CHEMICAL RESEARCH IN TOXICOLOGY,2014,27(6):1030-1039. |
| APA | Ruan, Jianqing,Yang, Mengbi,Fu, Peter,Ye, Yang,&Lin, Ge.(2014).Metabolic Activation of Pyrrolizidine Alkaloids: Insights into the Structural and Enzymatic Basis.CHEMICAL RESEARCH IN TOXICOLOGY,27(6),1030-1039. |
| MLA | Ruan, Jianqing,et al."Metabolic Activation of Pyrrolizidine Alkaloids: Insights into the Structural and Enzymatic Basis".CHEMICAL RESEARCH IN TOXICOLOGY 27.6(2014):1030-1039. |
入库方式： OAI收割
来源：上海药物研究所
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