Abstract
Aim: Fructus aurantii (FA) is widely used in clinic as an expectorant and digestant herb in traditional Chinese medicine and proven to have a variety of pharmacological functions. FA is close to grapefruit either by botanical taxonomy or by their same components (flavonoids, etc.) and grapefruit has been proven to cause drug–drug interaction when co-administrated with CYP3A4 substrates. Besides, FA contains many compounds, such as flavonoids, which have been reported to impact the expressions of CYP450. However, the effect of FA on CYP450, whose change may affect drug safety and clinical efficacy attributed to drug–drug interaction, still remains unknown.Methods: The protein, mRNA expression and enzyme activity of CYP1A2, CYP3A4, and CYP2E1 in rat were determined by Western Blotting, RT-PCR method, the cocktail method, respectively, after orally administration of FA in succession for 7 days. CYP1A2, CYP3A4, and CYP2E1 mRNA expression were investigated in HepG2 cells following FA-medicated serum incubation for 24 h.Results: In rat, compared to the control group, CYP1A2, CYP3A4 protein, and mRNA expression were significantly induced consistent with the corresponding CYP activities; the protein expression of CYP2E1 was significantly upregulated, while the corresponding mRNA expression and enzyme activity showed no significant change. In HepG2 cells, compared to the control group, the mRNA expression of CYP1A2 and CYP3A4 was up-regulated statistically while CYP2E1 mRNA expression was not significantly induced or inhibited.Conclusion: FA may be a potential slight inducer of CYP1A2 and CYP3A4 and is unlikely to impact CYP2E1 until clinical researches are conducted.
Highlights
Fructus aurantii (FA, Zhiqiao in Chinese), the dried and immature fruit of Citrus aurantium L. (Rutaceae) or its cultivars gathered from July, is used as an expectorant and digestant herb in traditional Chinese medicine, which is cited in Chinese Pharmacopoeia (1 part) of 2015 version
Among the Cytochrome P450 enzymes, families 1–3 constitute almost half of total CYPs in mammals (Bièche et al, 2007; Tydén et al, 2014), and CYP1A2, CYP2E1, and CYP3A4 were mainly expressed in the liver (Bièche et al, 2007), which is the major site of Cytochrome P450 mediated metabolism (Wilkinson, 2005)
CYP1A2 and CYP3A4 protein expression was significantly induced in all treatment conditions
Summary
Fructus aurantii (FA, Zhiqiao in Chinese), the dried and immature fruit of Citrus aurantium L. (Rutaceae) or its cultivars gathered from July, is used as an expectorant and digestant herb in traditional Chinese medicine, which is cited in Chinese Pharmacopoeia (1 part) of 2015 version. (Rutaceae) or its cultivars gathered from July, is used as an expectorant and digestant herb in traditional Chinese medicine, which is cited in Chinese Pharmacopoeia (1 part) of 2015 version It is widely used in clinic as one component of several formulae, such as Xue-Fu-Zhu-Yu Tang. FA extract is reported to have a wide range of potential therapeutic effects, such as hypocholesterolemic action (Kim et al, 2011), anti-tumor action (Zhou et al, 2007), prokinetic action (Huang et al, 2011; Zhang et al, 2012), anti-ischemic action (Kang et al, 2007), and anti-depressive action (Fan et al, 2012; Zhang et al, 2012). The well-known example is that grapefruit juice increases the bioavailability of various drugs due to the inhibition of CYP3A4 metabolism (Yoshida et al, 2005)
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