Probe-substrate assay reveals the inhibition of CYP1A2, 2C9, and 3A4 by Senkyunolide A in human liver microsomes.

Abstract

Senkyunolide A (Sen A) has been shown to have neuroprotective effects, which leads to its inclusion in the daily diet of the elderly, thereby increasing the risk of adverse interactions with other drugs. To offer a reference for the clinical prescription and administration of Sen A, its impact on the activity of cytochrome P450 enzymes (CYP450s) was investigated.Pooled human liver microsomes were utilised to conduct the probe substrate assay. Concentration-dependent and time-dependent evaluation was carried out with 0 - 100 μM of Sen A and incubation time of 0-30 min. The inhibition of CYP450s was fitted with competitive or non-competitive inhibition models to characterise the effects of Sen A.Sen A significantly inhibited the activities of CYP1A2, 2C9, and 3A4 with IC₅₀ values of 16.59, 14.73, and 11.51 μM, respectively. Both the inhibition of CYP1A2 and 2C9 followed a competitive pattern with the Ki values of 7.08 and 6.56 μM, respectively. In contrast, the inhibition of CYP3A4 was non-competitive (Ki = 5.19 μM) and time-dependent with the KI and K_inact of 0.404 μM^-1 and 0.013 min^-1, respectively.Careful administration of Sen A and related herbs is advised when used concurrently with drugs metabolised by CYP1A2, 2C9, and 3A4.