Effects of Dibutyl phthalate and Di(2-ethylhexyl) phthalate with their metabolites on CYP2C9*1 and CYP2C19*1 activities in vitro

In this study, recombinant CYP2C9*1 and CYP2C19*1 microsomes were used to investigate the effects of phthalates and their metabolites on corresponding enzyme activities in vitro. 2-100 μM substrate of enzyme was incubated with series concentration of phthalates for 30 min at 37 °C. The metabolic products were detected using ultra-high performance liquid chromatography (UHPLC) and ultra-high performance liquid chromatography-mass spectrometry (UHPLC-MS/MS) methods. The results showed dibutyl phthalate (DBP) significantly inhibited CYP2C9*1 with an activity inhibition rate of 67.3% and half-maximal inhibitory concentration (IC50) of 29.63 μmol L–1, but its metabolite monobutyl phthalate (MBP) had no significant effect. On the other hand, di(2-ethylhexyl)phthalate (DEHP) had no effect on CYP2C9*1, but its metabolite monoethylhexyl phthalate (MEHP) significantly inhibited the enzyme activity with an activity inhibition rate of 90.6% and IC50 of 6.37 μmol·L–1. With regards to CYP2C19*1, DBP completely inhibited the enzyme activity with an activity inhibition rate of 100% and IC50 of 2.63 μmol L–1, but its metabolite MBP had no effect on it. DEHP and MEHP also inhibited the activity of CYP2C19*1. Further investigation showed MEHP was a competitive inhibitor of CYP2C9*1 (Ki = 7.063 μmol·L–1), and DBP was a competitive inhibitor of CYP2C19*1 (Ki&thinsp...
Source: Journal of Pharmaceutical and Biomedical Analysis - Category: Drugs & Pharmacology Source Type: research

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