In vitro inhibitory effects of bergenin on human liver cytochrome P450 enzymes

Context Anemarsaponin BII is one of the most active saponins isolated from Anemarrhena asphodeloides Bunge (Asparagaceae), a commonly used Chinese traditional paediatric medicine. Objective This study investigates the effects of anemarsaponin BII on the activity of CYP450s to provide more guidance for the clinical use of anemarsaponin BII. Materials and methods Using various diagnostic substrates, the effects of a fixed concentration of anemarsaponin BII (100 μM) on the activity of eight main isoforms of CYP450s (CYP1A2, 2A6, 3A4, 2C8, 2C9, 2C19, 2D6 and 2E1) was first studied with pooled human liver microsomes (HLMs). Then, dose-dependent (0, 2.5, 5, 10, 25, 50 and 100 μM anemarsaponin BII) and time-dependent (0, 5, 10, 15 and 30 min) experiments were performed to obtain corresponding kinetic parameters. Results Anemarsaponin BII showed significant inhibitory effects on the activity of CYP3A4, 2D6 and 2E1 with the IC 50 values of 13.67, 16.26 and 19.72 μM. Anemarsaponin BII acted as a non-competitive inhibitor of CYP3A4 with the K I value of 6.72 μM and competitive inhibitors of CYP2D6 and 2E1 with the K I values of 8.26 and 9.82 μM, respectively. Additionally, the inhibition of CYP3A4 was revealed to be time-dependent with the K I value of 4.88 μM and the K inact value of 0.053/min. Conclusions The inhibitory effect of anemarsaponin BII on the activity of CYP3A4, 2D6 and 2E1 indicated the potential drug–drug interaction between anemarsaponin BII and drugs metabolized by these CYP450s. Further in vivo experiments are needed to validate the potential drug–drug interactions.

“…The effect of anemarsaponin BII on the activity of CYPs was evaluated in pooled human liver microsomes according to previous studies (Dong et al. 2018 ; Wang et al. 2019 ).…”

Section: Methodsmentioning

confidence: 99%

Anemarsaponin BII inhibits the activity of CYP3A4, 2D6, and 2E1 with human liver microsomes

Wang

Jiang

Zhou

et al. 2020

“… 2009 ; Dong et al. 2018 ). Drug-drug interactions induced by changes of CYP450 activity were also assessed in many studies (Yamamoto et al.…”

Section: Introductionmentioning

confidence: 99%

“…CYP450 enzymes can be transcriptionally activated or inhibited by various xenobiotics and endogenous substrates. Previously, a number of herbs have been reported to exert inhibitory effects on the activity of CYP450 enzymes, such as bergenin, pulvinic acid, and natural furanocoumarins (Guo et al 2000;Huang et al 2009;Dong et al 2018). Drug-drug interactions induced by changes of CYP450 activity were also assessed in many studies (Yamamoto et al 2017;Giri et al 2018;Nishihara et al 2019).…”

Section: Introductionmentioning

confidence: 99%

In vitro study on the effect of peucedanol on the activity of cytochrome P450 enzymes

Zhang

Yin

et al. 2021

Context: Peucedanol is a major extract of Peucedanum japonicum Thunb. (Apiaceae) roots, which is a commonly used herb in paediatrics. Its interaction with cytochrome P450 enzymes (CYP450s) would lead to adverse effects or even failure of therapy. Objective: The interaction between peucedanol and CYP450s was investigated. Materials and methods: Peucedanol (0, 2.5, 5, 10, 25, 50, and 100 lM) was incubated with eight human liver CYP isoforms (CYP1A2, 2A6, 3A4, 2C8, 2C9, 2C19, 2D6, and 2E1), in pooled human liver microsomes (HLMs) for 30 min with specific inhibitors as positive controls and untreated HLMs as negative controls. The enzyme kinetics and time-dependent study (0, 5, 10, 15, and 30 min) were performed to obtain corresponding parameters in vitro. Results: Peucedanol significantly inhibited the activity of CYP1A2, 2D6, and 3A4 in a dose-dependent manner with IC 50 values of 6.03, 13.57, and 7.58 lM, respectively. Peucedanol served as a non-competitive inhibitor of CYP3A4 with a K i value of 4.07 lM and a competitive inhibitor of CYP1A2 and 2D6 with a K i values of 3.39 and 6.77 lM, respectively. Moreover, the inhibition of CYP3A4 was time-dependent with the K i /K inact value of 5.44/0.046 min/lM. Discussion and conclusions: In vitro inhibitory effect of peucedanol on the activity of CYP1A2, 2A6, and 3A4 was reported in this study. As these CYPs are involved in the metabolism of various drugs, these results implied potential drug-drug interactions between peucedanol and drugs metabolized by CYP1A2, 2D6, and 3A4, which needs further in vivo validation.

“…2017; Dong et al. 2018). In vitro P450 enzyme inhibition assays have been routinely used to assess the P450-mediated drug-drug interactions (DDI) potential of these enzymes.…”

Section: Introductionmentioning

confidence: 99%

In vitro inhibitory effects of kaempferitrin on human liver cytochrome P450 enzymes

Zhang

Liu

Chen

et al. 2019

Context: Kaempferitrinis (KF) is a bioactive flavonoid and possesses numerous pharmacological activities. However, whether KF affects the activity of human liver cytochrome P450 (CYP) enzymes remains unclear. Objective: This study investigates the effects of KF on eight major CYP isoforms in human liver microsomes (HLMs). Materials and methods: In vitro, HLMs were used to investigate the inhibitory effects of KF (100 lM) on the eight human liver CYP isoforms (i.e., 1A2, 3A4, 2A6, 2E1, 2D6, 2C9, 2C19, and 2C8), and corresponding probe substrates were used. Enzyme kinetic studies (0-50 lM of KF) were conducted to determine the inhibition mode of KF on CYP enzymes. Results: The results showed that KF inhibited the activity of CYP1A2, 3A4, and 2C9, with IC 50 values of 20.56, 13.87, and 14.62 lM, respectively, but that other CYP isoforms were not affected. Enzyme kinetic studies showed that KF was not only a noncompetitive inhibitor of CYP3A4, but also a competitive inhibitor of CYP1A2 and 2C9, with Ki values of 7.11, 10.24, and 7.58 lM, respectively. In addition, KF is a timedependent inhibitor for CYP3A4 with K I /K inact value of 10.85/0.036 min/lM. Discussion: The in vitro studies of KF with CYP isoforms indicate that KF has the potential to cause pharmacokinetic drug interactions with other co-administered drugs metabolized by CYP1A2, 3A4, and 2C9. Conclusion: It is recommended that KF should not be used with other drugs metabolized by CYP1A2, 3A4, and 2C9. Further clinical studies are needed to evaluate the significance of this interaction.