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Osthol (OST) has a wide range of pharmacological effects and has long been used in clinical medicine in China. Previous studies have indicated that osthol has weak inhibitory effects on CYP3A4 in human liver microsomes. The aim of the present study was to investigate the inhibition of Cyp3a by osthol in rats in vivo. A substrate assay was used to corroborate the inhibitory effect on Cyp3a by osthol in rats, and the substrate probe (midazolam) was detected by high-performance liquid chromatography (HPLC). Semi-quantitative RT-PCR (SqRT-PCR) analysis was used to study the effect of osthol on Cyp3a1 and Cyp3a2 mRNA expression and Western blot analysis was used to investigate the effect of OST on Cyp3a1 and Cyp3a2 protein expression. Our study confirmed the inhibitory effect of osthol on Cyp3a and indicated that the inhibitory effect on Cyp3a was stronger in the group receiving multiple doses compared with the single dose group. The SqRT-PCR analysis results showed that medium and high doses of osthol (20 and 40 mg/kg, respectively) had an inhibitory effect on Cyp3a1 mRNA expression but not on Cyp3a2 mRNA expression. Western blot analysis results indicated that the inhibitory effect of the medium and high osthol doses on Cyp3a1 and Cyp3a2 protein expression was significantly different. It was also demonstrated that the inhibitory effect of osthol on Cyp3a in rats resulted from the comprehensive effect of the direct inhibition of the Cyp3a enzyme, as well as the down-regulation of its mRNA and protein expression level.
Mark Gales (Mon,) studied this question.