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Inhibitory Effects of Schisandra Lignans on Cytochrome P450s and Uridine 50-Diphospho-Glucuronosyl Transferases in Human Liver Microsomes

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Inhibitory Effects of Schisandra Lignans on Cytochrome P450s and Uridine 50-Diphospho-Glucuronosyl Transferases in Human Liver Microsomes pharmaceutics Article Inhibitory Effects of Schisandra Lignans on Cytochrome P450s and Uridine 50-Diphospho-Glucuronosyl Transferases in Human Liver Microsomes Hyung-Ju Seo 1, Seung-Bae Ji 1, Sin-Eun Kim 1, Gyung-Min Lee 1, So-Young Park 1, Zhexue Wu 2, Dae Sik Jang 3,* and Kwang-Hyeon Liu 1,2,* 1 BK21 FOUR Community-Based Intelligent Novel Drug Discovery Education Unit, College of Pharmacy and Research Institute of Pharmaceutical Sciences, Kyungpook National University, Daegu 41566, Korea; [email protected] (H.-J.S.); [email protected] (S.-B.J.); [email protected] (S.-E.K.); [email protected] (G.-M.L.); [email protected] (S.-Y.P.) 2 Mass Spectrometry Based Convergence Research Institute and Department of Chemistry, Kyungpook National University, Daegu 41566, Korea; [email protected] 3 Department of Life and Nanopharmaceutical Sciences, Kyung Hee University, Seoul 02447, Korea * Correspondence: [email protected] (D.S.J.); [email protected] (K.-H.L.); Tel.: +82-2-961-0719 (D.S.J.); +82-53-950-8567 (K.-H.L.) Abstract: Schisandra chinensis has been widely used as a traditional herbal medicine to treat chronic coughs, fatigue, night sweats, and insomnia. Numerous bioactive components including lignans have been identified in this plant. Lignans with a dibenzocyclooctadiene moiety have been known Citation: Seo, H.-J.; Ji, S.-B.; Kim, to possess anti-cancer, anti-inflammatory, and hepatoprotective activity. Fragmentary studies have S.-E.; Lee, G.-M.; Park, S.-Y.; Wu, Z.; reported the ability of some lignans to modulate some cytochrome P450 (P450) enzymes. Herein, Jang, D.S.; Liu, K.-H. Inhibitory we investigated the drug interaction potential of six dibenzocyclooctadiene lignans (schisandrin, Effects of Schisandra Lignans on gomisin A, B, C, and N, and wuweizisu C) on nine P450 enzymes (CYP1A2, 2A6, 2B6, 2C8, 2C9, Cytochrome P450s and Uridine 2C19, 2D6, 2E1, and 3A) and six uridine 50-diphosphoglucuronosyl transferase (UGT) enzymes 50-Diphospho-Glucuronosyl (UGT1A1, 1A3, 1A4, 1A6, 1A9, and 2B7) using human liver microsomes. We found that lignans Transferases in Human Liver with one or two methylenedioxyphenyl groups inhibited CYP2B6, CYP2C8, CYP2C9, CYP2C19, and Microsomes. Pharmaceutics 2021, 13, 371. https://doi.org/10.3390/ CYP2E1 activities in a time- and concentration-dependent like their CYP3A inhibition. In comparison, pharmaceutics13030371 these lignans do not induce time-dependent inhibition of CYP1A2, CYP2A6, and CYP2D6. The time-dependent inhibition of gomisin A against CYP2C8, CYP2C19, and CYP3A4 was also elucidated Academic Editor: José using glutathione as a trapping reagent of reactive carbene metabolites given that gomisin A strongly Martínez Lanao inhibits these P450 enzymes in a time-dependent manner. A glutathione conjugate of gomisin A was generated in reactions with human recombinant CYP2C8, CYP2C19, and CYP3A4. This suggests Received: 4 February 2021 that the time-dependent inhibition of gomisin A against CYP2C8, CYP2C9, and CYP3A4 is due to Accepted: 2 March 2021 the production of carbene reactive metabolite. Six of the lignans we tested inhibited the activities Published: 10 March 2021 of six UGT to a limited extent (IC50 > 15 µM). This information may aid the prediction of possible drug interactions between Schisandra lignans and any co-administered drugs which are mainly Publisher’s Note: MDPI stays neutral metabolized by P450s. with regard to jurisdictional claims in published maps and institutional affil- Keywords: Schisandra chinensis; lignans; cytochrome P450; uridine 50-diphosphoglucuronosyl iations. transferase; drug interaction Copyright: © 2021 by the authors. 1. Introduction Licensee MDPI, Basel, Switzerland. This article is an open access article Herb drug interactions (HDI) which result in serious adverse events have received sig- distributed under the terms and nificant attention with the increased use of alternative medicines as well as the widespread conditions of the Creative Commons use of combination therapies for various diseases in recent years [1,2]. The underlying Attribution (CC BY) license (https:// mechanisms of HDI mainly involve the modulation of cytochrome P450 (P450) and uridine 0 creativecommons.org/licenses/by/ 5 -diphosphoglucuronisyl transferase (UGTs) enzyme activities [2,3]. For example, Saint 4.0/). John’s Wort, a well-studied example of such an HDI, and hyperforin is thought to be the Pharmaceutics 2021, 13, 371. https://doi.org/10.3390/pharmaceutics13030371 https://www.mdpi.com/journal/pharmaceutics Pharmaceutics 2021, 13, x FOR PEER REVIEW 2 of 14 Pharmaceutics 2021, 13, 371 uridine 5′-diphosphoglucuronisyl transferase (UGTs) enzyme activities [2,3]. For example,2 of 14 Saint John’s Wort, a well-studied example of such an HDI, and hyperforin is thought to be the main component that modulates CYP3A and CYP2C9 enzymes [4]. Many well- mainknown component herbal medicines that modulates including CYP3A ginseng and [5,6], CYP2C9 ginkgo enzymes [7], green [4 ].tea Many [8], and well-known Schisandra herbal[9] have medicines also been including reported ginseng to result [5, 6in], ginkgopharmacokinetic [7], green teadrug [8 ],interactions and Schisandra with[9 clinical] have alsodrugs. been In reporteda recent study, to result curcuma in pharmacokinetic was found to drugsignificantly interactions increase with the clinical urine drugs.metabolic In aratio recent of dextromethorphan/dextrorphan study, curcuma was found to significantly by inhibiting increase CYP2D6 the [10]. urine metabolic ratio of dextromethorphan/dextrorphanSchisandra chinensis Bailon (Schisandraceae), by inhibiting CYP2D6 a climbing [10]. plant distributed in Asia (Ko- rea, SchisandraJapan, and chinensis China) [11]Bailon and (Schisandraceae), its fruits, known aas climbing omija in plantKorea, distributed have been in extensively Asia (Ko- rea,used Japan, in traditional and China) herbal [11 ]medicine and its fruits, to treat known chronic as omijacoughs, in enuresis, Korea, have fatigue, been night extensively sweats, usedand insomnia in traditional [12]. herbal In clinical medicine settings, to treat however, chronic co-administration coughs, enuresis, fatigue,of Schisandra night sweats,extracts andor their insomnia components [12]. In clinicalwith other settings, therapeuti however,c drugs co-administration may lead to HDIs. of Schisandra For example,extracts Schi- or theirsandra components extracts markedly with other increased therapeutic the blood drugs conc mayentration lead to HDIs. of taclolimus For example, by inhibitingSchisandra the extractsCYP3A markedlyenzyme in increased liver transplant the blood patients concentration [9]. Gomisin of taclolimus N, one by of inhibiting the most the abundant CYP3A enzymelignans inisolated liver transplant from the patientsfruits of [S.9]. chinensis Gomisin, has N, one also of been the mostshown abundant to increase lignans the iso-oral latedbioavailability from the fruits of drugs of S. metabolized chinensis, has by also CYP3A, been shown including to increase midazolam the oral in rats bioavailability [13]. There- offore, drugs dibenzocyclooctadiene metabolized by CYP3A, lignans, including the major midazolam active components in rats [13]. of Therefore, S. chinensis dibenzocy-, may ac- clooctadienecount for some lignans, HDIs. the The major major active lignans components in the fruits of ofS. S. chinensis chinensis, may are accountgomisin forA, some-B, -C, HDIs.and -N, The as major well as lignans schisandrin in the fruitsand wuweizisu of S. chinensis C (Figureare gomisin 1), with A, -B, schisandrin -C, and -N, being as well the asmost schisandrin abundant, and accounting wuweizisu for C33 (Figure−45% of1 the), with total schisandrin lignans in omija being (S. the chinensis most abundant,) fruits [14– accounting16]. for 33−45% of the total lignans in omija (S. chinensis) fruits [14–16]. FigureFigure 1.1. ChemicalChemical structures structures of of the the six six lignans: lignans: (a) gomisin (a) gomisin A, (b A,) gomisin (b) gomisin B, (c) B,gomisin (c) gomisin C, (d) C, gomisin N, (e) schisandrin, and (f) wuweizisu C. (d) gomisin N, (e) schisandrin, and (f) wuweizisu C. AA fewfew inin vitrovitro studiesstudies investigating the the modulatory modulatory effects effects of of individual individual dibenzocy- dibenzo- cyclooctadieneclooctadiene lignans lignans on on P450 P450 enzyme enzyme activities activities have have been been carried carried out. out. For Forexample, example, pre- previousvious studies studies found found that that gomisin gomisin A, A,-C, -C, an andd -G -G inhibit inhibit CYP3A-mediated CYP3A-mediated midazolam midazolam 1′- 0 μ μ μ 1hydroxylation-hydroxylation with with IC IC50 50valuesvalues of of 1.86 1.86 µM,M, 0.059 0.059 µM,M, and 0.19 µM inin aa recombinantrecombinant CYP3A4CYP3A4 isoform,isoform, respectivelyrespectively [17[17,18],,18], whilewhile schisandrin schisandrin AA inhibits inhibits CYP2C19-catalyzed CYP2C19-catalyzed μ omeprazoleomeprazole hydroxylation hydroxylation with with an an IC IC50 50of of 86.4 86.4µM M in in recombinant recombinant CYP2C19 CYP2C19 [19 ].[19]. Moreover, Moreo- schisandrinver, schisandrin and gomisinand gomisin A were A were found found to inhibit to inhibit recombinant recombinant CYP3A4 CYP3A4 activity activity with ICwith50 values of 32.0 and 1.39 µM, respectively [20]. Iwata et al. (2004) also evaluated the effects of six lignans including schisandrin, gomisin A, and -N on P450 activities, however, their inhibitory effects were estimated for only five P450s (1A2,
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