Interactions of neocryptotanshinone and human cytochrome P450 in silico and in vitro

Neocryptotanshinone (NCTS), an ingredient of Salviae Miltiorrhizae Radix et Rhizoma, is a promising compound for development since it exhibits various pharmacological effects including hypoglycemic and anti-inflammatory activities. In this study, we aimed to elucidate the interactions between NCTS and cytochrome P450s (CYPs), including the CYP-mediated NCTS metabolism and NCTS-induced CYP regulation. The results revealed that NCTS was mainly metabolized by CYPs in human liver microsomes (HLMs), and CYP2C8 and 2C9 were identified as the main CYPs involved; the relative contributions of CYP2C8 and 2C9 were 35 % and 65 %, respectively, after normalization of individual CYP abundance in the human liver. Meanwhile, NCTS weakly inhibited CYP1A2, 2C8, and 2C9, with IC 50  > 30 μM. In addition, NCTS induced CYP2B6 and CYP3A4 expression in human primary hepatocytes, and the underlying mechanism was found by the activation of the pregnane X receptor (PXR) vis reporter gene assay. Molecular docking of NCTS and CYPs, PXR confirmed these results. Our study sheds light on the interactions of NCTS with CYPs and provides useful information for predicting potential drug-drug interactions for NCTS, which will be helpful for NCTS development and clinical utilization of drugs containing NCTS.