Characterization of an epoxide‐derived metabolite of dictamnine using high‐performance liquid chromatography with hybrid linear trap quadrupole orbitrap mass spectrometry

Abstract

Dictamnine (4-methoxyfuro[2,3-b]quinolone), a furoquinoline alkaloid of the Rutaceae plant family, has been reported to be a phototoxic and photomutagenic compound, whose exposure can cause carcinogenicity, cytotoxicity, and genotoxicity. Metabolic activation is suggested to play an important role in dictamnine-induced toxicities, and the epoxide metabolite of dictamnine has been reported to be the main intermediate in vitro. The objective of this study was to identify N-acetylcysteine conjugate(s) derived from this reactive dictamnine metabolite in vitro and in vivo. An N-acetylcysteine conjugate of dictamnine was detected in microsomal incubations of dictamnine, as well as bile and urine samples of rats treated with dictamnine. The data obtained from the present work will facilitate the understanding of the mechanism behind dictamnine-induced toxicities.

Metabolic Profile of Skimmianine in Rats Determined by Ultra-Performance Liquid Chromatography Coupled with Quadrupole Time-of-Flight Tandem Mass Spectrometry

“…After the oral administration of skimmianine to rats, plasma, urine, and feces samples were collected, extracted, and analyzed as described. The metabolites were predicted by using MetabolitePilot TM software and then confirmed manually based on the above fragmentation pathways of the skimmianine standard and the literature [ 21 , 22 , 23 ]. A total of 16 metabolites were identified in the biological samples originating from rats ( Table 1 ).…”

“…The Phase II metabolism included glucuronidation and sulfation of some Phase I metabolites. The Phase I metabolic pathways were similar to those of dictamnine, which was also a furoquinoline alkaloid [ 21 , 22 , 23 ]. It seemed that the epoxidation of 2,3-olefinic on the furan ring followed by the hydrolysis of its epoxide ring was a typical characteristic of the furoquinoline alkaloid metabolism.…”

Simultaneous analysis of tropane alkaloids in teas and herbal teas by liquid chromatography coupled to high‐resolution mass spectrometry (Orbitrap)

“…When the benchtop Exactive‐Orbitrap mass spectrometer was launched in 2008 , ultra‐high resolving power (100 000 full‐width at half maximum (FWHM)) has become a power tool for the analysis of different mycotoxins , plant toxins , or alkaloids . However, methods for the determination of TAs based on LC with full‐scan high‐resolution (Orbitrap) MS are scarce, although some of them were applied to determine TAs in food and feed and herbal extracts .…”

The Modulatory Role of CYP3A4 in Dictamnine-Induced Hepatotoxicity

“…A previous study found that CYP3A4 was the metabolic enzyme mediating bioactivation of the furan ring in toosendanin and yielded a cis -butene-1,4-dial intermediate ( Yu et al, 2014 ). Considering the molecular structure of DTN possessing a furan ring and was primarily metabolic activated by CYP3A4 ( Feng et al, 2016 ), the present study attempted to define the role of CYP3A4 in DTN-induced hepatotoxicity.…”

“…More importantly, it was confirmed that DTN was predominantly metabolized into an epoxide intermediate (2,3-epoxide) in vitro , which was primarily in the participation of CYP3A4 ( Wang et al, 2016 ). Furthermore, the epoxide intermediate could subsequently conjugated with N -acetylcysteine to form conjugate with CYP3A4 was primarily responsible for the metabolic activation process ( Feng et al, 2016 ). Thus, evidences have shown the link between the metabolic activation of DTN and CYP3A4, namely CYP3A4 was the predominant enzyme involved in the metabolism of DTN.…”