Effects of Schizonepetin on Activity and mRNA Expression of Cytochrome P450 Enzymes in Rats

Beihua Bao,Anwei Ding,Yudan Cao,Li Zhang,Weifeng Yao,Ting Geng

doi:10.3390/ijms131217006

Beihua Bao, Anwei Ding + Show 4 more

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https://doi.org/10.3390/ijms131217006

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Abstract

The aim of this study was to find out whether Schizonepetin influences the pharmacokinetics of the main substrates drugs of CYP1A2, CYP3A1/2, CYP2E1, CYP2C19 and CYP2D6 in rats; the influence on the levels of CYP mRNA was also studied. Phenacetin, dapsone, chlorzoxazone, omeprazole and metoprolol were selected as probe substrates for CYP1A2, CYP3A1/2, CYP2E1, CYP2C19 and CYP2D6 respectively. HPLC methods were employed for the determination of these substrates in plasma and the pharmacokinetic parameters were calculated. Real-time RT-PCR was used to determine the effects of Schizonepetin on the mRNA expression of CYP3A1, CYP1A2 and CYP2E1 in the rat liver. After the rats were orally administrated with Schizonepetin once a day for seven consecutive days, there were significant differences in plasma concentration of phenacetin, dapsone, chlorzoxazone and metoprolol, but not omeprazole, as compared with pre-administration. In addition, Schizonepetin induced the expression of CYP3A1, CYP1A and CYP2E1 at dosages of 24 and 48 mg/kg. Our results indicated that Schizonepetin had significant induction effects on CYP3A1/2 and inhibition effects on CYP1A2, CYP2E1 or CYP2D6 as oriented from the pharmacokinetic profiles of the substrates. Moreover, in the mRNA expression levels, Schizonepetin could induce the mRNA expression of CYP3A1, CYP1A and CYP2E1. In conclusion, co-administration of some CYP substrates with Schizonepetin may lead to an undesirable herb-drug interaction.

Highlights

Herba Schizonepetae (“Jingjie” in Chinese) originated from dried aerial parts of Schizonepeta tenuifolia Briq. has been frequently and widely used in the treatment of colds and high fevers in China for centuries [1]
The pharmacokinetic profiles of dapsone before and after oral administration of Schizonepetin for seven days were shown in Table 1 and Figure 2
Our results indicated that CYP3A1/2 activity significantly induced by Schizonepetin after multiple oral administrations in rats

Summary

Introduction

Herba Schizonepetae (“Jingjie” in Chinese) originated from dried aerial parts of Schizonepeta tenuifolia Briq. has been frequently and widely used in the treatment of colds and high fevers in China for centuries [1]. Schizonepetin (Figure 1), a natural monoterpene, was the main component and was first isolated from the essential oil of S. tenuifolia in our laboratory [2]. It possessed various pharmacological effects, including excellent antiviral, anti-inflammatory and analgesic activities [2,3], while without obvious toxicity of the respiratory, cardiovascular and nervous systems in rats and dogs [4]. In acute and subacute toxicity studies, it has been found that the median lethal orally dose of Schizonepetin was 478 mg/kg in mice and the no observed adverse effect level in rat was 120 mg/kg/day [5,6]

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