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

Abstract

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 pharmacokinetic study on the interaction between nobiletin and anemarsaponin BII in vivo and in vitro

“… 2020 ), and anemarsaponin BII was also revealed to inhibit the activity of CYP3A4 in a dose-dependent manner with the IC 50 value of 10.23 μM in the present study, which is consistent with the previous study (Wang M et al. 2020 ). Hence, the inhibition of CYP3A4 was speculated to be one of the potential mechanisms underlying the interaction of nobiletin with anemarsaponin BII.…”

“… 2020 ; Wang M et al. 2020 ). The rats in the nobiletin group were orally administrated with 50 mg/kg nobiletin alone.…”

Human liver microsomes study on the inhibitory effect of plantainoside D on the activity of cytochrome P450 activity

“…The activity of P450s was evaluated by corresponding metabolites using HPLC with Agilent 1260 Series Rapid Resolution HPLC. The reaction system was prepared with the following compositions: HLMs with certain protein concentrations, specific substrates of different isoenzymes, PBS buffer solution, plantainoside D or specific inhibitors, and an NADPH generating system as previously reported [ 16 , 17 ]. Besides dextromethorphan and quinidine were dissolved in water, other substrated, inhibitors, and plantainoside D were dissolved in methanol with a final concentration of 1% (v/v).…”

Hepatic, Extrahepatic and Extracellular Vesicle Cytochrome P450 2E1 in Alcohol and Acetaminophen-Mediated Adverse Interactions and Potential Treatment Options

“…Cepharanthine, a biscoclaurine alkaloid, has been shown to prevent DDI via CYP2E1 in vitro human liver microsomes [ 71 ]. Anemarsaponin BII (ABII) is an active saponin and competitive inhibitor of CYP2E1 activity with half-maximal inhibitory concentration (IC50) and dissociation constant (Ki) values of 19.72 μM and 9.82 μM, respectively, suggesting a DDI between ABII and drugs metabolized by CYP2E1 [ 72 ]. A study conducted on rats and hepatic cells revealed that anti-tuberculosis drugs, such as rifampicin and isoniazid, induce liver injury by regulating the nucleotide-binding domain (NOD)-like receptor protein 3 (NLRP3) inflammasome and enhancing CYP2E1 mRNA expression [ 73 ].…”