Inhibitory effect of imperatorin and isoimperatorin on activity of cytochrome P450 enzyme in human and rat liver microsomes

Cao, Yan; Zhong, Yu-Huan; Yuan, Ming; Li, Hua; Zhao, Chunjie

doi:10.4268/cjcmm20130823

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CJCMM

2013

DOI: 10.4268/cjcmm20130823

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Inhibitory effect of imperatorin and isoimperatorin on activity of cytochrome P450 enzyme in human and rat liver microsomes

Yan Cao

Yu-Huan Zhong²,

Ming Yuan³

et al.

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Cited by 3 publications

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Inhibition of Caffeine Metabolism by Apiaceous and Rutaceae Families of Plant Products in Humans: In Vivo and In Vitro Studies

2021

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Daily consumption of caffeinated beverages is considered safe but serious health consequences do happen in some individuals. The Apiaceous and Rutaceae families of plant (ARFP) products are popular foods and medicines in the world. We previously reported significant amounts of furanocoumarin bioactive such as 8-methoxypsoralen, 5-methoxypsoralen, and isopimpinellin in ARFP products. As both caffeine and furanocoumarin bioactive are metabolized by the same hepatic CYP1A1/2 isozyme in humans, caffeine/ARFP product interactions may occur after co-administration. The objectives of the present study were to study in vivo loss of caffeine metabolizing activity by comparing the pharmacokinetics of caffeine in volunteers before and after pre-treatment with an ARFP extract, study the correlation between the decrease in hepatic CYP1A2 activity and the content of furanocoumarin bioactive in ARFP extracts, characterize CYP1A2 inactivation using in vitro incubations containing 14C-caffeine, a furanocoumarin bioactive, and human liver microsomes (HLMs), and provide a mechanistic explanation for both in vivo and in vitro data using the irreversible inhibition mechanism. The study results showed pre-treatment of volunteers with four ARFP extracts increased the area-under-the-concentration-time-curve (AUC0-inf) ratio of caffeine in the plasma ranging from 1.3 to 4.3-fold compared to the untreated volunteers indicating significant caffeine metabolism inhibition. The increases in AUC0-inf ratio also were linearly related to the effect-based doses of the furanocoumarins in the ARFP extracts, a finding which indicated caffeine metabolism inhibition was related to the content of furanocoumarin bioactive in an ARFP product. In vitro incubation studies also showed individual furanocoumarin bioactive were potent inhibitors of caffeine-N-demethylation; the IC50 for 8-methoxypsoralen 5-methoxypsoralen, and isopimpinellin were 0.09, 0.13, and 0.29 µM, respectively. In addition, CYP1A2 inactivation by individual furanocoumarin bioactive was concentration- and time-dependent involving the irreversible inhibition mechanism. The proposed irreversible inhibition mechanism was investigated further using 14C-labeled 8-methoxypsoralen and HLMs. The formation of 14C-adducts due to 14C-8-MOP-derived radioactivity bound to HLMs confirmed the irreversible inhibition of CYP1A2 activity. Thus, furanocoumarin bioactive metabolism in humans would result in reactive metabolite(s) formation inactivating CYP1A2 isozyme and inhibiting caffeine metabolism. Once the CYP1A2 isozyme was deactivated, the enzymic activity could only be regained by isozyme re-synthesis which took a long time. As a result, a single oral dose of ARFP extract administered to the human volunteers 3.0 h before still was able to inhibit caffeine metabolism.

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Inhibition of Caffeine Metabolism by Apiaceous and Rutaceae Families of Plant Products in Humans: In Vivo and In Vitro Studies

2021

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Pharmacokinetics and Brain Distribution of the Active Components of DA-9805, Saikosaponin A, Paeonol and Imperatorin in Rats

et al. 2018

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DA-9805 is a botanical anti-Parkinson’s drug candidate formulated from ethanol extracts of the root of Bupleurum falcatum, the root cortex of Paeonia suffruticosa, and the root of Angelica dahurica. The pharmacokinetics (PKs) and brain distribution of active/representative ingredients of DA-9805, Saikosaponin a (SSa; 1.1–4.6 mg/kg), Paeonol (PA; 14.8–59.2 mg/kg), and Imperatorin (IMP; 1.4–11.5 mg/kg) were evaluated following the intravenous or oral administration of each pure component and the equivalent dose of DA-9805 in rats. All three components had greater dose-normalized areas under the plasma concentration-time curve (AUC) and slower clearance with higher doses, following intravenous administration. By contrast, dose-proportional AUC values of SSa, PA, and IMP were observed following the oral administration of each pure component (with the exception of IMP at the highest dose) or DA-9805. Compared to oral administration of each pure compound, DA-9805 administration showed an increase in the AUC of SSa (by 96.1–163%) and PA (by 155–164%), possibly due to inhibition of their metabolism by IMP or other component(s) in DA-9805. A delay in the absorption of PA and IMP was observed when they were administered as DA-9805. All three components of DA-9805 showed greater binding values in brain homogenates than in plasma, possibly explaining why the brain-to-plasma ratios were greater than unity following multiple oral administrations of DA-9805. By contrast, their levels in cerebrospinal fluid were negligible. Our results further our understanding of the comprehensive PK characteristics of SSa, PA, and IMP in rats and the comparative PKs between each pure component and DA-9805.

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An updated phytopharmacological review on medicinal plant of arab region: Apium graveolens Linn

Alasmari

Athar

Kadasah³

2017

Phcog Rev

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Apium graveolens Linn. (Karafs) is used in traditional medicine for the treatment of the various ailments. There is a need to explore and authenticate the pharmacological profile and medicinal importance of the Karafs. In this paper, the literature and the published work on Apium were collected using online resources “Google scholar”, “Web of science”, “Scopus” and “PubMed”. Each of the pharmacological activity was searched individually using the keywords “Apium/Karafs/Apium graveolens + individual pharmacological activity”. We documented the most cited and most recent literatures. The current findings illuminate the importance Karafs in the traditional medicine and their impact in treating various diseases. This review strongly supports the fact that the Apium has emerged as a good source of medicine in treating various diseases. There is also a need to isolate the bioactive phytochemicals present in this plant.

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Inhibitory effect of imperatorin and isoimperatorin on activity of cytochrome P450 enzyme in human and rat liver microsomes

Cited by 3 publications

References 0 publications

Inhibition of Caffeine Metabolism by Apiaceous and Rutaceae Families of Plant Products in Humans: In Vivo and In Vitro Studies

Inhibition of Caffeine Metabolism by Apiaceous and Rutaceae Families of Plant Products in Humans: In Vivo and In Vitro Studies

Pharmacokinetics and Brain Distribution of the Active Components of DA-9805, Saikosaponin A, Paeonol and Imperatorin in Rats

An updated phytopharmacological review on medicinal plant of arab region: Apium graveolens Linn

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