Identification of the Metabolic Enzyme Involved Morusin Metabolism and Characterization of Its Metabolites by Ultraperformance Liquid Chromatography Quadrupole Time‐of‐Flight Mass Spectrometry (UPLC/Q‐TOF‐MS/MS)

Abstract

Morusin, the important active component of a traditional Chinese medicine, Morus alba L., has been shown to exhibit many vital pharmacological activities. In this study, six recombinant CYP450 supersomes and liver microsomes were used to perform metabolic studies. Chemical inhibition studies and screening assays with recombinant human cytochrome P450s were also used to characterize the CYP450 isoforms involved in morusin metabolism. The morusin metabolites identified varied greatly among different species. Eight metabolites of morusin were detected in the liver microsomes from pigs (PLMs), rats (RLMs), and monkeys (MLMs) by LC-MS/MS and six metabolites were detected in the liver microsomes from humans (HLMs), rabbits (RAMs), and dogs (DLMs). Four metabolites (M1, M2, M5, and M7) were found in all species and hydroxylation was the major metabolic transformation. CYP1A2, CYP2C9, CYP2D6, CYP2E1, CYP3A4, and CYP2C19 contributed differently to the metabolism of morusin. Compared to other CYP450 isoforms, CYP3A4 played the most significant role in the metabolism of morusin in human liver microsomes. These results are significant to better understand the metabolic behaviors of morusin among various species.

The Beneficial Effects of Morusin, an Isoprene Flavonoid Isolated from the Root Bark of Morus

“…Morusin displayed broad inhibitory activities against several lipoxygenases, while artonin E, produced by hydroxylation at C-5′ of morusin, displayed inhibitory activity against 5-lipoxygenase higher by one order of magnitude [ 19 ]. Molecular docking analysis between morusin and the cytochrome isoform CYP3A4 indicated that oxygens in the pyran ring, C-5 and C-2′ are involved in hydrogen bonds with CYP3A4 and the B ring structure of morusin is involved in π-π interaction with Phe108 of CYP3A4 [ 16 , 20 ]. Hydrogen bond formation between the 2′-hydroxy group of morusin and Tyr393 of MMP-9 and cation-pi interactions between the flavone backbone of morusin and Tyr423 of MMP-9 were also associated with morusin binding to MMP-9 [ 21 ].…”

“…Such findings may be clinically relevant, since these enzymes have been implicated in the dysregulation of lipid homeostasis and endoplasmic reticulum stress, which play key roles in the pathogenesis of various metabolic disorders including diabetes [ 62 , 63 ]. Of note, CYP450 and other ER-resident lipid oxygenases including CYP1A2, CYP2C9, CYP2D6, CYP2E1, CYP3A4 and CYP2C19 have been proposed as metabolizing enzymes of morusin per se [ 17 , 20 ], although it is unclear whether the mechanisms contribute to the drug resistance or whether the intermediates mediate the beneficial effects of morusin.…”

The Pro-Health Benefits of Morusin Administration—An Update Review

“…Shi et al [ 25 ] described their in vitro study on the liver metabolism of morusin. The metabolites are listed in Table 2 , whereas their chemical structures and proposed metabolic pathways are presented in Figure 3 .…”

Preparation of a Sensor Based on Biomass Porous Carbon/Covalent-Organic Frame Composites for Pesticide Residues Detection

“…Conventional analytical techniques, like HPLC and gas chromatography, mostly combined with mass-selective detectors (Liu et al, 2017 ; Song et al, 2019a ), are slow and costly. These approaches are still carried out in laboratories (Shi et al, 2016a ; Liu et al, 2017 ; Su et al, 2018 ) butthey are not appropriate for quick field detection (Su et al, 2014 ; Song et al, 2019b ). Therefore, the fabrication of rapid and sensitive OPs detection strategies with fewer limitations are increasingly desired by the food industry and for environmental monitoring.…”