Inhibitory effects of dioscin on cytochrome P450 enzymes

Abstract

Dioscin, a natural product, shows various pharmacological activities. However, the drug–drug interaction (DDI) potential of dioscin via the inhibition of cytochrome P450 (CYP) enzymes is still unknown. In this paper, the inhibitory effects of dioscin on six major CYP isoforms (1A2, 2A6, 2C9, 2D6, 2E1 and 3A4) were investigated. Using human liver microsomes (HLM), we found that dioscin inhibited the activities of CYP2C9, CYP2E1 and CYP3A4, with IC₅₀ values of 22.60, 17.40 and 12.59 μM, respectively. Further research indicated that dioscin was a typical competitive inhibitor for CYP2C9, CYP2E1 and CYP3A4 (K_i = 5.0, 10.4 and 15.5 μM, respectively), as demonstrated by Lineweaver–Burk plots. In addition, dioscin exhibited time- and NADPH-dependent inhibitions of CYP3A4, and weak inhibitions of CYP1A2, CYP2A6 and CYP2D6 were also observed. In cell and animal experiments, dioscin markedly down-regulated the protein expressions of CYP2C9, CYP2E1 and CYP3A4 in primary rat hepatocytes and livers in a dose-dependent manner. This is the first paper on the inhibitory effects of dioscin on CYP in HLMs to predict the potential for dioscin–drug interaction and toxicity. Nevertheless, the clinical significance of the data presented herein should be further evaluated with in vivo research.