Abstract
Dictamnine (4-methoxyfuro[2,3-b]quinolone, DIC), a common furoquinoline alkaloid in the family of Rutaceae, showed diverse biological activities. To investigate the in vivo metabolic pathways of DIC, metabolism of DIC in mice was studied using a high-performance liquid chromatography coupled to electrospray ionization of hybrid linear trap quadrupole orbitrap (HPLC-LTQ-Orbitrap) mass spectrometer. Nine metabolites were identified in the DIC-treated mouse urine, plasma, and fecal samples, of which two were identified as new metabolites. The major metabolic pathways of DIC in animal and human liver microsomes were confirmed in the present study, including o-demethylation, monohydroxylation, N-oxidation, and 2,3-olefinic epoxidation pathways. For the first time, a mono-acetylcysteine conjugate of DIC (M9) was detected from DIC-treated mouse urine and plasma samples, and 4-methoxy-2-oxo-1,2-dihydroquinoline-3-carboxylic acid (M10) and 2-(2,8-dihydroxy-4-methoxyquinolin-3-yl)acetaldehyde (M11) were identified as new metabolites of DIC; furthermore, using an in vitro human fecal incubation model, furo[2,3-b]quinolin-4-ol (M1) was verified to be a microbial demethylated metabolite of DIC. Collectively, the present study provided new information on the in vivo metabolic fate of DIC.
Highlights
Dictamnine (4-methoxyfuro[2,3-b]quinolone, DIC), a common furoquinoline alkaloid in the family of Rutaceae, showed diverse biological activities, such as antifungal, antibacterial, vascular-relaxing, antiplatelet aggregation, and antihypertension activities [1,2,3,4,5,6,7]
Very recently, using in vitro microsomal incubation systems, we systematically studied the metabolites of DIC in human and animal liver microsomal incubation systems [14], and we found that the metabolic fate of DIC in human liver microsomes was about the same as that in mouse liver microsomes, while with some differences compared with that in rat, dog, and monkey liver microsomes
HPLCLTQ-Obitrap/MS was used to explore the major metabolites of DIC in samples
Summary
Dictamnine (4-methoxyfuro[2,3-b]quinolone, DIC), a common furoquinoline alkaloid in the family of Rutaceae, showed diverse biological activities, such as antifungal, antibacterial, vascular-relaxing, antiplatelet aggregation, and antihypertension activities [1,2,3,4,5,6,7]. DIC exhibits potent cytotoxic activity against human cervix, colon, breast, and lung cancer cell lines, and the main mechanism is by inhibiting cell proliferation and promoting cell apoptosis [8, 9]. Liang et al reported that DIC as an anticancer agent arrests cells in the S phase of the cell cycle and induces human lung adenocarcinoma A549 cell apoptosis via the mitochondria-mediated caspase-independent pathway [10]. Novel synthetic and semisynthetic derivatives of DIC, as potential antitumor agents, have gained increasing attention in medicinal research [11]. In a separate study [15], a N-acetylcysteine (NAC) conjugate which was derived from the reactive DIC metabolite, Journal of Analytical Methods in Chemistry
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