1-Formyl-7-hydroxy-6,7-dihydro-5H-pyrrolizine (9-CHO-DHP) - A Biologically Proximate Pyrrolic Metabolite of Carcinogenic Pyrrolizidine Alkaloids
Refereed conference paper presented and published in conference proceedings

香港中文大學研究人員

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摘要Pyrrolizidine alkaloids (PAs) are phytochemical constituents of more than 6000 plant species worldwide; approximately 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 the metabolic activation pathway of PA-induced liver tumor initiation is mediated by a set of four (±)-6,7-dihydro-7-hydroxy-1-hydroxymethyl-5H-pyrrolizine (DHP)-derived DNA adducts, and proposed that these DHP-DNA adducts are potential 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 important to identify the spectrum of reactive metabolites associated with this metabolic activation pathway. Segall et al. (Drug Metab. Disposit., 12, 68-71, 1984) reported that 1-formyl-7-hydroxy-6,7-dihydro-5H-pyrrolizine (9-CHO-DHP) is a metabolite formed from the mouse liver microsomal metabolism of senecionine. In this present study, we examined the metabolism of six hepatocarcinogenic PAs (riddelliine, senecionine, monocrotaline, senkirkine, intermedine, and heliotrine) and one non-carcinogenic PA (platphylline) by human, rat, and mouse liver microsomes. 9-CHO-DHP was found as a common metabolite from the metabolism of the six hepatocarcinogenic PAs, but not from platphylline. Incubation of 9-CHO-DHP in HepG2 cells and A549 cells resulted in the formation of the same set of DHP-DNA adducts, as assessed by both LC/MS SRM mode and selected ion monitoring analyses through comparison to synthetic standards. In the incubation medium of HepG2 cells, both DHP and 7-cysteine-DHP were identified. These metabolites have previously shown to be capable of binding to cellular DNA to produce DHP-DNA adducts. Thus, when incubated with HepG2 cells, 9-CHO-DHP was metabolized to the reactive metabolites DHP and 7-cysteine-DHP, metabolites associated with the DHP-DNA adduct formation. These results indicate that 9-CHO-DHP is a DNA proximate metabolite of hepatotoxic PAs and further support the generality of this metabolic activation pathway mediated by the formation of these DHP-DNA adducts.
著者Qingsu XIA, Xiaobo HE, Ge LIN, Peter P. FU
會議名稱Experimental Biology Meeting 2018
會議開始日21.04.2018
會議完結日25.04.2018
會議地點San Diego, California
會議國家/地區美國
會議論文集題名FASEB JOURNAL
出版年份2018
月份4
卷號32
期次Supp 1
國際標準期刊號0892-6638
電子國際標準期刊號1530-6860
語言美式英語

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