Abstract
Context: Friedelin is a triterpenoid with several biological activities. However, the affects of Friedelin on the activity of human liver cytochrome P450 (CYP) enzymes remains unclear.Objective: This study investigates the inhibitory effects of Friedelin on the major human liver CYP isoforms (CYP3A4, 1A2, 2A6, 2E1, 2D6, 2C9, 2C19 and 2C8).Materials and methods: First, the inhibitory effects of Friedelin (100 μM) on the eight human liver CYP isoforms were investigated in vitro using human liver microsomes (HLMs), and then enzyme inhibition, kinetic studies, and time-dependent inhibition studies were conducted to investigate the IC50, Ki and Kinact/KI values of Friedelin.Results: The results indicate that Friedelin inhibited the activity of CYP3A4 and 2E1, with the IC50 values of 10.79 and 22.54 μM, respectively, but other CYP isoforms were not affected. Enzyme kinetic studies showed that Friedelin is not only a noncompetitive inhibitor of CYP3A4, but also a competitive inhibitor of CYP2E1, with Ki values of 6.16 and 18.02 μM, respectively. In addition, Friedelin is a time-dependent inhibitor of CYP3A4 with Kinact/Ki value of 4.84 nM/min.Discussion and conclusion: The in vitro studies of Friedelin with CYP isoforms suggested that Friedelin has the potential to cause pharmacokinetic drug interactions with other co-administered drugs metabolized by CYP3A4 and 2E1. Further clinical studies are needed to evaluate the significance of this interaction.
Highlights
Friedelin is a triterpenoid isolated from the leaves of Maytenus ilicifolia (Mart.) ex
To investigate whether Friedelin affects the catalytic activity of Cytochrome P450 (CYP) enzymes, the probe reaction assays were conducted with varying concentrations of Friedelin
As Friedelin possesses numerous pharmacological activities, has a wide range of applications in the clinic, it is essential to investigate the inhibitory effects of Friedelin on the major CYP enzymes
Summary
Friedelin is a triterpenoid isolated from the leaves of Maytenus ilicifolia (Mart.) ex. Multiple-drug therapy possess several advantages, and many herb–drug interactions resulting from concurrent use of herbal drugs with prescription and over-the-counter drugs may cause adverse reactions such as toxicity and treatment failure (Zhang et al 2007; Grimm et al 2009; Jeong et al 2013; Lee et al 2013; Qi et al 2013; Meng and Liu 2014). The effects of Friedelin on the activity of CYP enzymes should be investigated. To the best of our knowledge, no studies have been performed to investigate the effects of Friedelin on the major CYP enzymes, the inhibitory effects, which will increase the risk of therapeutic applications of Friedeli and its medical preparations
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