The inhibition of tricin on human liver cytochrome P450 enzymes

Tricin has attracted increasing attention due to its diverse pharmacological properties, highlighting its considerable potential for clinical application. However, its potential for drug–drug interactions (DDIs) and its inhibitory effects on human cytochrome P450 (CYP450) enzymes remain unclear. This study aimed to explore the effect of tricin on CYP450s. The inhibitory effect of tricin on CYP450s was evaluated by an in vitro study using human pooled live microsomes (HLMs). Tricin, CYP450 enzymes, and the corresponding substrates were co-incubated with HLMs using a NADPH-generating system, and the HLMs incubated without tricin or positive inhibitors served as the negative control. Corresponding inhibitory parameters were obtained by incubating tricin (0-100 µM) with the specific substrates at different concentrations. Tricin showed a selective inhibitory effect on the activities of CYP1A2, 2D6, and 3A4, with the IC 50 values of 12.760 µM, 14.050 µM, and 6.925 µM for CYP3A4 with testosterone as substrate, and 8.070 µM for CYP3A4 with midazolam as substrate, respectively. It was revealed that tricin competitively inhibited the activities of CYP1A2 ( K i =5.641 µM) and 2D6 ( K i =6.247 µM) while non-competitively inhibited the activity of CYP3A4 ( K i =2.876 µM). The activity of CYP3A4 was also inhibited by tricin in a time-dependent inhibition (TDI) manner with a K I of 1.418 µM and a K inact of 0.029 min⁻¹. In vitro HLM study indicated the competitive inhibition of tricin on CYP1A2 and 2D6, while non-competitive inhibition and TDI on CYP3A4, thereby informing its potential for clinical drug interactions. Not applicable.