1-Formyl-7-hydroxy-6,7-dihydro-5 H-pyrrolizine (1-CHO-DHP): A Potential Proximate Carcinogenic Metabolite of Pyrrolizidine Alkaloids.,Chemical Research in Toxicology

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1-Formyl-7-hydroxy-6,7-dihydro-5 H-pyrrolizine (1-CHO-DHP): A Potential Proximate Carcinogenic Metabolite of Pyrrolizidine Alkaloids.
Chemical Research in Toxicology ( IF 3.7 ) Pub Date : 2019-06-03 , DOI: 10.1021/acs.chemrestox.9b00038
Xiaobo He ₁ , Qingsu Xia ₁ , Gonçalo Gamboa da Costa ₁ , Ge Lin ₂ , Peter P Fu ₁

Affiliation

Pyrrolizidine alkaloids (PAs) are phytochemicals present in more than 6000 plant species worldwide; about half of the PAs are hepatotoxic, genotoxic, and carcinogenic. Because of their wide exposure and carcinogenicity, the International Programme on Chemical Safety (IPCS) concluded that PAs are a threat to human health and safety. We recently determined that PA-induced liver tumor initiation is mediated by a set of four (±)-6,7-dihydro-7-hydroxy-1-hydroxymethyl-5 H-pyrrolizine (DHP)-DNA adducts and proposed that these DHP-DNA adducts are biomarkers of PA exposure and liver tumor initiation. To validate the generality of this metabolic activation pathway and DHP-DNA adducts as biomarkers, it is significant to identify reactive metabolites associated with this metabolic activation pathway. Segall et al. ( Segall et al. ( 1984 ) Drug Metab. Dispos. 12 , 68 - 71 ) previously reported that 1-formyl-7-hydroxy-6,7-dihydro-5 H-pyrrolizine (1-CHO-DHP) is generated from the metabolism of senecionine by mouse liver microsomes. In the present study, we examined the metabolism of seven hepatocarcinogenic PAs (senecionine, intermedine, retrorsine, riddelliine, DHR, heliotrine, and senkirkine) and one noncarcinogenic PA (platyphylline) by human, rat, and mouse liver microsomes. 1-CHO-DHP was identified as a common metabolite from the metabolism of these hepatotoxic PAs, but not from platyphylline. Incubation of 1-CHO-DHP with HepG2 and A549 cells produced the same set of DHP-DNA adducts, which were identified by both LC/MS MRM mode and selected ion monitoring analyses through comparison to synthetic standards. In the incubation medium of 1-CHO-DHP treated HepG2 cells, both DHP and 7-cysteine-DHP were formed, which were capable of binding to cellular DNA to produce DHP-DNA adducts. These results suggest that 1-CHO-DHP is a proximate DNA metabolite of genotoxic and carcinogenic PAs.

中文翻译：

1-甲酰基-7-羟基-6,7-二氢-5 H-吡咯烷嗪（1-CHO-DHP）：吡咯烷核生物碱的潜在致癌代谢物。

吡咯烷核生物碱（PAs）是世界范围内超过6000种植物中存在的植物化学物质。大约一半的PA具有肝毒性，遗传毒性和致癌性。由于其广泛的暴露范围和致癌性，国际化学安全计划（IPCS）得出结论，PA是对人类健康和安全的威胁。我们最近确定，PA诱导的肝肿瘤起始是由一组四个（±）-6,7-dihydro-7-hydroxy-1-hydroxymethyl-5 H-吡咯烷嗪（DHP）-DNA加合物介导的，并建议这些DHP -DNA加合物是PA暴露和肝肿瘤发生的生物标志物。为了验证该代谢活化途径和DHP-DNA加合物作为生物标记的一般性，重要的是鉴定与该代谢活化途径相关的反应性代谢产物。Segall等。（Segall等人（1984）Drug Metab.Dispos。12、68-71）先前报道了1-甲酰基-7-羟基-6,7-二氢-5H-吡咯烷嗪（1-CHO-DHP）是由小鼠肝脏微粒体的新芥子碱的代谢产生的。在本研究中，我们研究了人，大鼠和小鼠肝微粒体对7种肝癌PA（西尼西宁，中间药物，逆转录酶，riddelliine，DHR，血统碱和senkirkine）和1种非致癌PA（白茶碱）的代谢。从这些肝毒性PA的代谢中，1-CHO-DHP被确定为常见的代谢产物，而从茶碱中则没有。将1-CHO-DHP与HepG2和A549细胞一起孵育可产生相同的DHP-DNA加合物，可通过LC / MS MRM模式和与合成标准品进行比较的选定离子监测分析进行鉴定。在1-CHO-DHP处理过的HepG2细胞的培养液中，形成了DHP和7-半胱氨酸-DHP，它们能够结合细胞DNA以产生DHP-DNA加合物。这些结果表明1-CHO-DHP是遗传毒性和致癌PA的近DNA代谢产物。

更新日期：2019-05-23

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