Abstract
Adverse side effects of drug-drug interactions induced by human cytochrome P450 (CYP450) inhibition is an important consideration in drug discovery. Mulberry leaves are of broad popular use for food or remedy purposes, which is believed to contain substances that are beneficial for preventing and alleviating diabetes. However, there is a paucity of information about the effect of mulberry leaves on rat CYP450 enzymes activities and the mRNA expression levels in vivo. The present study aimed to investigate the effect of mulberry leaves on activities of rat CYP450 enzymes (CYP3A4, CYP2C8, CYP2C19, CYP2D6, and CYP1A2) through both probe-drug cocktail approach and real-time polymerase chain reaction (RT-qPCR). The pharmacokinetic results indicated that the aqueous extract of mulberry leaves (AML) exhibited induction effects on CYP3A4 activities, and AML exhibited inhibitory effects on CYP1A2, CYP2D6, and CYP2C8, while no obvious effect was observed on CYP2C19 activity. Additionally, the ethanol extract of mulberry leaves (EML) could induce the activities of CYP3A4. In addition, EML exhibited inhibitory effects on CYP1A2, CYP2D6, and CYP2C19, while no significant change in CYP2C8 activity was observed. Accordingly, the level of mRNA expression of five CYP enzymes were consistent with the result of pharmacokinetic. The results of our study may form a practical strategy for assessing CYP-mediated HDI.
Highlights
Mulberry leaf (Folium mori) pertains to dried leaves of the Morus alba L. plant (Joh et al, 2015) known to be rich in flavonoids, alkaloids, polysaccharides, volatile oils, and other active components
Among the several cytochrome P450 (CYP450) isoforms identified to date, human CYP3A4, CYP1A2, CYP2D6, CYP2C19, and CYP2C8 metabolize over 90% clinical drugs (Rendic S, Di Carlo FJ, 1997; Reginald EF, 2004)
For establishing safety of usage in clinical combinations, we evaluated the influence of mulberry leaf extracts on the activities of five CYP450 subtypes based on changes in pharmacokinetic parameters in an in vivo rat model using specific probe drugs, compared to a control group
Summary
Mulberry leaf (Folium mori) pertains to dried leaves of the Morus alba L. plant (family Moraceae) (Joh et al, 2015) known to be rich in flavonoids, alkaloids, polysaccharides, volatile oils, and other active components. MSA, Chilkunda ND, 2018; Zheng et al, 2017; Wang et al, 2015). Owing to their multiple beneficial effects, mulberry leaves are commercially used in the formulation of nutraceuticals, tea supplements, cosmetics and functional foods in Asia. Among the several CYP450 isoforms identified to date, human CYP3A4, CYP1A2, CYP2D6, CYP2C19, and CYP2C8 metabolize over 90% clinical drugs (Rendic S, Di Carlo FJ, 1997; Reginald EF, 2004). Inhibition or stimulation of CYP activity is a potential cause of the diverse pharmacokinetics of drugs, resulting in unexpected and even serious clinical herb-drug interactions (HDI). HDIs may lead to toxicity or poor efficacy of drugs
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