Abstract
Context Ganoderic acid A (GAA) is usually used to prevent cancers or other diseases, which make it likely to be used with other drugs metabolized by cytochromes P450. Objective This study investigates the effect of GAA on eight major cytochrome P450 isoforms in human liver microsomes. Material and method The effects of GAA (100 μM) on eight human liver CYP isoforms (i.e., 1A2, 3A4, 2A6, 2E1, 2D6, 2C9, 2C19, and 2C8) were investigated in vitro using human liver microsomes (HLMs) with specific substrates for the CYPs, and the enzyme kinetic parameters were calculated. Results The results showed that GAA inhibited the activity of CYP3A4, 2D6, and 2E1, but did not affect other isoforms. The inhibition of CYP3A4, 2D6, and 2E1 was concentration-dependent with IC50 values of 15.05, 21.83, and 28.35 μM, respectively. Additionally, GAA was not only a non-competitive inhibitor of CYP3A4, but also a competitive inhibitor of CYP2D6 and 2E1, with Ki values of 7.16, 10.07, and 13.45 μM. Meanwhile, the inhibition of CYP3A4 was time-dependent, with the KI/Kinact value of 7.91/0.048 μM/min. Discussion and conclusion The in vitro study indicated that GAA has the potential to result in drug-drug interactions with other drugs metabolized by CYP3A4, 2D6, and 2E1. Further clinical studies are needed for the identification of this interaction.
Highlights
Cytochrome P450 enzymes (CYPs) are one of the most important phase-I enzymes that participate in the metabolism of most clinical drugs in liver and intestine
The results showed that Ganoderic acid A (GAA) significantly inhibited the activity of CYP3A4, 2D6, and 2E1 to 14.6, 18.2, and 27.7% of their negative control, but did not exert effect on the activity of other CYPs
The results of the enzyme inhibition and kinetic studies showed the inhibitory effect of GAA on the activity of CYP3A4, 2D6, and 2E1
Summary
Cytochrome P450 enzymes (CYPs) are one of the most important phase-I enzymes that participate in the metabolism of most clinical drugs in liver and intestine. Previous studies demonstrated glycyrrhizic acid, verapamil, and grapefruit juice have effects on the pharmacokinetics of other drugs during the drugdrug interaction through inhibiting the activity of CYPs (Huang et al 2018; Jia et al 2018; Zhao et al 2018). Numerous studies report CYPs are responsible for the bioactivation and inactivation of carcinogens and anticancer drugs (RodriguezAntona and Ingelman-Sundberg 2006; Mittal et al 2015). CYP2E1 acts an important role in the metabolism and activation of the carcinogens related to colorectal cancer (Jiang et al 2013). Many drugs have been reported to have an inhibitory effect on the activity of CYPs, such as bergenin, isofraxidin and kaempferitrin (Dong et al 2018; Song et al 2019; Zhang et al 2019)
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