26 May 2020 : Laboratory Research
CYP2C9, a Metabolic CYP450s Enzyme, Plays Critical Roles in Activating Ellagic Acid in Human Intestinal Epithelial Cells
Yang Gu1BCDEF, Wei Hou1BCDEF, Xin-yu Shen1BCDE, Shi-xuan Zhuo1BCDF, Hao-ran Zhang1BCF, Ming-hui Ji2BCF, Mei-juan Chen1ADG, Yuan-yuan Guo1ABDEG*DOI: 10.12659/MSM.923104
Med Sci Monit 2020; 26:e923104
Abstract
BACKGROUND: The metabolic processing of ellagic acid (EA) by cytochrome P450s (CYP450s) expressed in the intestines is unclear. This study aimed to investigate the effects of CYP450s that are highly expressed in HIEC cells on metabolic activity of EA.
MATERIAL AND METHODS: HIEC cell models expressing 2B6, 2C9, 2D6, and 3A4 were generated by stably transfecting with CYP450 genes using a lentivirus system. PCR and Western blot assay were used to detect expression of CYP450s. Cell Counting Kit-8 (CCK-8) assay was used to examine the cytotoxic effect of EA on CYP450s-expressing HIEC cells. Flow cytometry was employed to evaluate apoptosis of CYP450s-expressing HIEC cells after addition of EA. Metabolic clearance rate of EA in vitro by the constructed HIEC cell models was measured using UPLC-MS method.
RESULTS: CYP450s expression HIEC cell models, including CYP2B6, CYP2C9, CYP2D6, and CYP3A4, were successfully established. EA treatment at different concentrations (10 μg/mL and 50 μg/mL) remarkably decreased cell viability of HIEC cells expressing CYP2C9 compared to the untreated control (p<0.01), in a concentration-dependent and time-dependent manner. Expression of CYP2C9 significantly increased the apoptosis rate of HIEC cells treated with EA compared to that in HIEC cells without any CYP450s expression (p<0.01). The clearance rate of EA in CYP2B6-expressing (p<0.05) and CYP2C9-expressing (p<0.001) HIEC cell models was remarkably reduced after 120 min.
CONCLUSIONS: Ellagic acid was effectively activated by CYP2C9 in HIEC cells and caused cytotoxicity and apoptosis of HIEC cells. Therefore, CYP2C9 is main metabolic enzyme of EA when compared to other CYP450 HIEC cell models.
Keywords: Cytochrome P-450 Enzyme System, Ellagic Acid, Metabolic Clearance Rate, Cell Line, Chromatography, Liquid, Cytochrome P-450 CYP2C9, Cytochrome P-450 CYP2D6, Cytochrome P-450 CYP3A, Intestinal Mucosa, Intestines, tandem mass spectrometry
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