Lack of Metabolic Activation and Predominant Formation of an Excreted Metabolite of Nontoxic Platynecine-Type Pyrrolizidine Alkaloids
文献类型：期刊论文
| 作者 | Ruan, Jianqing2; Liao, Cangsong1,3,4,5; Ye, Yang1,3,4,5 ; Lin, Ge2,3,4
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| 刊名 | CHEMICAL RESEARCH IN TOXICOLOGY
 |
| 出版日期 | 2014-01 |
| 卷号 | 27期号:1页码:7-16 |
| ISSN号 | 0893-228X |
| DOI | 10.1021/tx4004159 |
| 文献子类 | Article |
| 英文摘要 | Pyrrolizidine alkaloid (PA) poisoning is well-known because of the intake of PA-containing plant-derived natural products and PA-contaminated foodstuffs. Based on different structures of the necine bases, PAs are classified into three types: retronecine, otonecine, and platynecine type. The former two type PAs possessing an unsaturated necine base with a 1,2-double bond are hepatotoxic due to the P450-mediated metabolic activation to generate reactive pyrrolic ester, which interacts with cellular macromolecules leading to toxicity. With a saturated necine base, platynecine-type PAs are reported to be nontoxic and their nontoxicity was hypothesized to be due to the absence of metabolic activation; however, the metabolic pathway responsible for their nontoxic nature is largely unknown. In the present study, to prove the absence of metabolic activation in nontoxic platynecine-type PM, hepatic metabolism of platyphylline (PLA), a representative platynecine-type PA, was investigated and directly compared with the representatives of two toxic types of PAs in parallel. By determining the pyrrolic ester-derived glutathione conjugate, our results confirmed that the major metabolic pathway of PLA did not lead to formation of the reactive pyrrolic ester. More interestingly, having a metabolic rate similar to that of toxic PAs, PLA also underwent oxidative metabolisms mediated by P450s, especially P450 3A4, the same enzyme that catalyzes metabolic activation of two toxic types of PAs. However, the predominant oxidative dehydrogenation pathway of PLA formed a novel metabolite, dehydroplatyphylline carboxylic acid, which. was water-soluble, readily excreted, and could not interact with cellular macromolecules. In conclusion, our study confirmed that the saturated necine bases determine the absence of metabolic activation and thus govern the metabolic pathway responsible for the nontoxic nature of platynecine-type PAS. |
| WOS关键词 | DNA-ADDUCTS ; LIVER MICROSOMES ; IN-VIVO ; CLIVORINE ; IDENTIFICATION ; RIDDELLIINE |
| 资助项目 | Research Grant Council of Hong Kong (GRF)[471310] ; Research Grant Council of Hong Kong (GRF)[469712] ; CUHK Direct Grant[2041744] |
| WOS研究方向 | Pharmacology & Pharmacy ; Chemistry ; Toxicology |
| 语种 | 英语 |
| WOS记录号 | WOS:000330205100002 |
| 出版者 | AMER CHEMICAL SOC |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/277320]  |
| 专题 | 新药研究国家重点实验室 中科院受体结构与功能重点实验室 |
| 通讯作者 | Lin, Ge |
| 作者单位 | 1.Chinese Acad Sci, Shanghai Inst Mat Med, Nat Prod Chem Dept, Beijing 100864, Peoples R China 2.Chinese Univ Hong Kong, Fac Med, Sch Biomed Sci, Hong Kong, Hong Kong, Peoples R China; 3.Chinese Acad Sci, Shanghai Inst Mat Med, Joint Res Lab Promoting Globalizat Tradit Chinese, Beijing 100864, Peoples R China; 4.Chinese Univ Hong Kong, Hong Kong, Hong Kong, Peoples R China; 5.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Beijing 100864, Peoples R China; |
| 推荐引用方式 GB/T 7714 | Ruan, Jianqing,Liao, Cangsong,Ye, Yang,et al. Lack of Metabolic Activation and Predominant Formation of an Excreted Metabolite of Nontoxic Platynecine-Type Pyrrolizidine Alkaloids[J]. CHEMICAL RESEARCH IN TOXICOLOGY,2014,27(1):7-16. |
| APA | Ruan, Jianqing,Liao, Cangsong,Ye, Yang,&Lin, Ge.(2014).Lack of Metabolic Activation and Predominant Formation of an Excreted Metabolite of Nontoxic Platynecine-Type Pyrrolizidine Alkaloids.CHEMICAL RESEARCH IN TOXICOLOGY,27(1),7-16. |
| MLA | Ruan, Jianqing,et al."Lack of Metabolic Activation and Predominant Formation of an Excreted Metabolite of Nontoxic Platynecine-Type Pyrrolizidine Alkaloids".CHEMICAL RESEARCH IN TOXICOLOGY 27.1(2014):7-16. |
入库方式： OAI收割
来源：上海药物研究所
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