Potential Metabolic Drug–Drug Interaction of Citrus aurantium L. (Rutaceae) Evaluating by Its Effect on 3 CYP450

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.

A Practical Perspective on the Use of Botanicals During the COVID-19 Pandemic: From Proven to Potential Interactions

“… 35 Moreover, a significant CYP3A4 and CYP1A2 induction was also observed in an in vivo animal study, showing a possible mixed effect on cytochromes. 36 Therefore, since large human clinical trials are still not available, caution should be exercised with the concomitant administration of C. aurantium derivatives and CYP3A4 metabolized drugs.…”

The Herb-Drug Pharmacokinetic Interaction of Fluoxetine and Its Metabolite Norfluoxetine with a Traditional Chinese Medicine in Rats by LC-MS/MS

“…Water extract of FA immature increased CYP3A4 protein expression and ethanol extract of FA immature induced CYP3A4 expression via the induction of PXR expression [45]. FA may be a potential minor inducer of CYP1A2 and CYP3A4 [46]. Related research shows that resveratrol may interfere with albumin binding of site II ligands and metabolism of drugs by CYP2C9 and/or CYP3A4 enzymes [47].…”

Network Analysis of the Herb–Drug Interactions of Citrus Herbs Inspired by the “Grapefruit Juice Effect”

“…GF inhibited intestinal and hepatic CYP3A4 in an exposure-dependent fashion, and patients taking CYP3A4 substrates are at risk of developing drug-related adverse events if consuming large amounts of GF . The GF-induced pharmacokinetic change of multiple drugs might be better explained by the impairment of CYP450 in the intestinal wall rather than in the liver. , In rats, FA upregulated the protein expression of CYP1A2, CYP3A4, and CYP2E1 and the mRNA expression of CYP1A2 and CYP3A4, which indicated that it might be a slight inducer of CYP1A2 and CYP3A4 . Besides, the extracts of FA and FAI showed mild inhibition on CYP3A .…”

“… 22 , 23 In rats, FA upregulated the protein expression of CYP1A2, CYP3A4, and CYP2E1 and the mRNA expression of CYP1A2 and CYP3A4, which indicated that it might be a slight inducer of CYP1A2 and CYP3A4. 24 Besides, the extracts of FA and FAI showed mild inhibition on CYP3A. 25 UGTs were a series of enzymes responsible for conjugative phase II reactions of drugs.…”