Tetracyclic triterpenoids as inhibitors of cytochrome P450 3A4 and their quantitative structure activity relationship analysis

Abstract

The interaction between herbs and clinical drugs is one of the risk factors for adverse drug reactions. In the present study, the inhibitory effects of 47 tetracyclic triterpenoids toward the main drug-metabolizing CYPs in humans were investigated. Most of the evaluated tetracyclic triterpenoids (TT) exhibited strong inhibitory effects toward CYP3A4 compared with other CYP subtypes. The inhibition kinetics of compounds 9 (23-acetyl alisol C), 44 (hemslecin A), and 47 (cucurbitacin E) against CYP3A4 were studied, and inhibition constant (Ki) was determined as 2.12, 0.196, and 0.162 µM, respectively. Some representative TT exhibited significant inhibitory effects toward the metabolism of gefitinib, atorvastatin, and quetiapine, indicating a potential interaction between TT derivatives and clinical drugs. Additionally, a quantitative structure–activity relationship (QSAR) study of a series of TT as inhibitors of CYP3A4 was performed. The present study provided key information to guide the rational use of herbs rich in TT.

Keywords

• Tetracyclic triterpenoids
• Cytochrome P450 3A4
• Structure-activity relationship
• Herbal-drug interactions
• Inhibition mechanism