Physcion inhibition of CYP2C9, 2D6 and 3A4 in human liver microsomes.

Context: The effect of the active ingredients in traditional Chinese medicines on the activity of cytochrome P450 enzymes (CYP450s) is a critical factor that should be considered in TCM prescriptions. Physcion, the major active ingredient of Rheum spp. (Polygonaceae), possesses wide pharmacological activities.

Objectives: The effect of physcion on CYP450 activity was investigated to provide a theoretical basis for use.

Materials and methods: The experiments were conducted in pooled human liver microsomes (HLMs). The activity of CYP450 isoforms was evaluated with corresponding substrates and probe reactions. Blank HLMs were set as negative controls, and typical inhibitors were employed as positive controls. The inhibition model was fitted with Lineweaver Burk plots. The concentration (0, 2.5, 5, 10, 25, 50 and 100 μM physcion) and time-dependent (0, 5, 10, 15 and 30 min) effects of physcion were also assessed.

Results: Physcion suppressed CYP2C9, 2D6 and 3A4 in a concentration-dependent manner with IC₅₀ values of 7.44, 17.84 and 13.50 μM, respectively. The inhibition of CYP2C9 and 2D6 was competitive with the K_i values of 3.69 and 8.66 μM, respectively. The inhibition of CYP3A4 was non-competitive with a K_i value of 6.70 μM. Additionally, only the inhibition of CYP3A4 was time-dependent with the K_I and K_inact parameters of 3.10 μM^-1 and 0.049 min^-1, respectively.

Conclusions: The inhibition of CYP450s by physcion should be considered in its clinical prescription, and the study design can be employed to evaluate the interaction of CYP450s with other herbs.