Add time:07/25/2019         Source:sciencedirect.com

The aim of this article is to assess the effect of phthalates on the activities of CYP2C9 and CYP2C19 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 = 7.013 μmol L–1) against their substrates, both phthalates were non-competitive inhibitors of the cofactor NADPH. Our results suggested that DBP, DEHP, and their metabolites exhibited significant inhibitory effects toward either CYP2C9*1 or CYP2C19*1. These findings provided valuable information for a potentially toxic mechanism of DEHP and DBP on endocrine disruption and a useful guidance for safe and effective usage of drugs in patients with long-term DEHP and DBP exposure.

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