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Inhibitory Effect of Sauchinone on UDP-Glucuronosyltransferase (UGT) 2B7 Activity

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Inhibitory Effect of Sauchinone on UDP-Glucuronosyltransferase (UGT) 2B7 Activity molecules Article Inhibitory Effect of Sauchinone on UDP-Glucuronosyltransferase (UGT) 2B7 Activity Byoung Hoon You, Eun Chae Gong and Young Hee Choi * College of Pharmacy and Intergrated Research Institute for Drug Development, Dongguk University-Seoul, 32 Dongguk-lo, Ilsandong-gu, Goyang, Gyonggi-do 10326, Korea; [email protected] (B.H.Y.); [email protected] (E.C.G.) * Correspondence: [email protected]; Tel.: +82-31-961-5212 Received: 4 January 2018; Accepted: 7 February 2018; Published: 9 February 2018 Abstract: Herb–drug interaction (HDI) limits clinical application of herbs and drugs, and inhibition of herbs towards uridine diphosphate (UDP)-glucuronosyltransferases (UGTs) has gained attention as one of the important reasons to cause HDIs. Sauchinone, an active lignan isolated from aerial parts of Saururus chinensis (Saururacease), possesses anti-oxidant, anti-inflammatory, and anti-viral activities. In pharmacokinetics of sauchinone, sauchinone is highly distributed to the liver, forming extensive metabolites of sauchinone via UGTs in the liver. Thus, we investigated whether sauchinone inhibited UGTs to explore potential of sauchinone–drug interactions. In human liver microsomes (HLMs), sauchinone inhibited activities of UGT1A1, 1A3, 1A6, and 2B7 with IC50 values of 8.83, 43.9, 0.758, and 0.279 µM, respectively. Sauchinone also noncompetitively inhibited UGT1A6 and 2B7 with Ki values of 1.08 and 0.524 µM, respectively. In in vivo interaction study using mice, sauchinone inhibited UGT2B7-mediated zidovudine metabolism, resulting in increased systemic exposure of zidovudine when sauchinone and zidovudine were co-administered together. Our results indicated that there is potential HDI between sauchinone and drugs undergoing UGT2B7-mediated metabolism, possibly contributing to the safe use of sauchinone and drug combinations. Keywords: sauchinone; Saururus chinensis; UGT2B7; inhibition; drug interaction 1. Introduction Herb–drug combinations have been steadily increased and encouraged as main medical treatments by the World Health Organization [1,2]. Since herb–drug interactions (HDIs) can limit clinical application of herbs and drugs, inhibition of herbs toward uridine diphosphate (UDP)-glucuronosyltransferases (UGTs) has received attention in association with alternations of drug efficacy or toxicity [3–5]. UGTs are phase II metabolic enzymes that predominantly catalyze glucuronidation of xenobiotics, including approximately 35% of drugs and consequently, facilitating elimination of glucuronidated metabolites through bile and urine [6,7]. Glucuronidation clears drugs because glucuronidated metabolites have more polarity and water solubility. It also detoxifies drugs because glucuronidated metabolites possess less activity or toxicity than their parent forms [8]. Many cases of UGT inhibition-mediated drug interactions have been reported [5,7] including UGT1A1 inhibition by psoralidin that causes irinotecan’ toxicity [9], UGT1A3 inhibition by gemfibrozil that enhances susceptibility of statins [10], UGT1A6 inhibition by silybin that attenuates fenofibrate-induced UGT1A6 [11], UGT1A6 inhibition by phenobarbital and phenytoin that causes hepatotoxicity of acetamoniphen [12,13], UGT1A9 inhibition by mefenamic acid that changes exposure of dapagliflozin’s metabolite [14], and UGT2B7 inhibition by valproic acid that changes efficacy and toxicity of zidovudine [15]. Regulatory agencies have recognized the importance of UGT-mediated drug Molecules 2018, 23, 366; doi:10.3390/molecules23020366 www.mdpi.com/journal/molecules Molecules 2018, 23, 366 2 of 13 Molecules 2017, 22, x FOR PEER REVIEW 2 of 12 interactionsresearch and in patients’ drug discovery safety [2,16,17]. research Moreover, and patients’ the safety U.S. FDA [2,16 ,strongly17]. Moreover, recommends the U.S. the FDA evaluation strongly recommendsof UGT-mediated the evaluation interactions of in UGT-mediated HDIs [3,16–18]. interactions in HDIs [3,16–18]. Saururus chinensis Hort. ex Loudon (Saururaceae), commonlycommonly known as Chinese lizard’s tail or Sam-baek-cho inin Korea,Korea, isis aa plantplant withwith aa long historyhistory ofof medical use.use. It has been used to treat hepatitis inin Korea [19,20] [19,20] and and edema, edema, pneumonia, pneumonia, jaundice, jaundice, gonorrhea gonorrhea and and inflammatory inflammatory disease disease in North in North Asia Asia[21]. [Sauchinone21]. Sauchinone is a isbiologically a biologically active active lignan lignan isolated isolated from from aerial aerial parts parts of of S.S. chinensis ,, showing anti-inflammatoryanti-inflammatory and anti-viral activities [[22,23].22,23]. In pharmacokinetic studies, sauchinone is highly distributed to to the the liver liver where where UGTs UGTs can can extensively extensively catalyze catalyze sauchinone sauchinone metabolism metabolism [24,25]. [24 Thus,,25]. Thus,there theremight might be potential be potential of sauchinone–drug of sauchinone–drug interact interactionion through through UGT-mediated UGT-mediated metabolism. metabolism. However, However, currently there isis nono informationinformation regarding inhibitioninhibition of UGTs byby sauchinone.sauchinone. Therefore,Therefore, thethe objectiveobjective of this study was was to to determine determine the the inhibitory inhibitory effect effect of ofsauchinone sauchinone on onUGT1A1, UGT1A1, 1A3, 1A3, 1A4, 1A4, 1A6, 1A6, 1A9, 1A9, and and2B7 2B7activities. activities. Inhibition Inhibition kinetics kinetics of sauchinone of sauchinone was then was theninvestigat investigateded in in invitroin vitrousingusing human human liver livermicrosomes microsomes (HLMs). (HLMs). Pharmacokine Pharmacokinetictic interaction interaction of ofsauchinone sauchinone and and zidovudine, zidovudine, a a substrate substrate of UGT2B7, waswas alsoalso evaluatedevaluated inin vivovivo usingusing mice.mice. 2. Results 2.1. Inhibitory Effects of Sauchinone on UGT ActivitiesActivities The inhibitoryinhibitory effects of sauchinonesauchinone on UGT1A1,UGT1A1, 1A3, 1A4, 1A6, 1A9, and 2B7 were shownshown in Figure1 1 and and their their IC IC5050 values are listed in Table1 1.. When When sauchinone sauchinone concentrations concentrations were were increased increased toto 200200 µμM,M, ICIC5050 valuesvalues ofof UGT1A1-catalyzedUGT1A1-catalyzed ββ-estradiol,-estradiol, UGT1A3-catalyzedUGT1A3-catalyzed CDCA,CDCA, 1A6-catalyzed1A6-catalyzed serotonin,serotonin, andand 2B7-catalyzed 2B7-catalyzed zidovudine zidovudine (8.83, (8.83, 43.9, 43.9, 0.758, 0.758, and and 0.279 0.279µM, μ respectively)M, respectively) were were lower lower than thosethan those of well-known of well-known inhibitors inhibitors such such as chrysin, as chrysin, lithocholic lithocholic acid, acid, 1-naphthol, 1-naphthol, and efavirenzand efavirenz (28.3, (28.3, 69.8, 35.2,69.8, and35.2, 75.4 andµ M75.4 respectively), μM respectively), indicating indicating that sauchione that sauchione inhibited inhibited metabolic metabolic activities ofactivities UGT1A1, of 1A3,UGT1A1, 1A6, and1A3, 2B7 1A6, in HLM.and 2B7 Sauchinone in HLM. also Sauchinone showed negligible also showed inhibitory negligible effect oninhibitory UGT1A4 effect and 1A9 on activitiesUGT1A4 underand 1A9 our activities study conditions. under our study conditions. 125 UGT1A1 125 UGT1A3 125 UGT1A4 100 100 100 75 75 75 50 50 50 25 25 25 0 0 0 -5 -4 -3 -2 -1 0 1 2 3 -5 -4 -3 -2 -1 0 1 2 3 -5 -4 -3 -2 -1 0 1 2 3 125 UGT1A6 125 UGT2B7 125 UGT1A9 100 100 100 % of control activity of control % 75 75 75 50 50 50 25 25 25 0 0 0 -5 -4 -3 -2 -1 0 1 2 3 -5 -4 -3 -2 -1 0 1 2 3 -5 -4 -3 -2 -1 0 1 2 3 Sauchinone (log μM) Figure 1. IC50 curves for the direct inhibition of UGT1A1, UGT1A3, UGT1A4, UGT1A6, UGT1A9, and Figure 1. IC50 curves for the direct inhibition of UGT1A1, UGT1A3, UGT1A4, UGT1A6, UGT1A9, and UGT2B7 in HLMs. The ‘•●’’ representsrepresents thethe remainingremaining percentagepercentage ofof UGT-mediatedUGT-mediated metabolicmetabolic activityactivity withwith sauchinonesauchinone asas anan inhibitorinhibitor versusversus controlcontrol (without(without sauchinone).sauchinone). ((nn == 33 forfor eacheach group).group). Molecules 2018, 23, 366 3 of 13 Table 1. IC50 (µM) values of sauchinone (n = 3 for each UGT isoform) and well-known inhibitors (n = 1 forMolecules each 2017 UGT, 22 isoform), x FOR PEER for REVIEW inhibition of various UGTs in human liver microsomes. Data were expressed3 of 12 as the mean values. The minimum and maximum values of IC50 were expressed in the parentheses. Table 1. IC50 (μM) values of sauchinone (n = 3 for each UGT isoform) and well-known inhibitors (n = 1 for each UGTUGTs isoform) for inhibition Sauchinone of various UGTs Well-Known in human Inhibitorliver microsomes. Data were expressed as the mean values. The minimum and maximum values of IC50 were expressed in the UGT1A1 8.83 (5.40–14.5) Chrysin 28.3 parentheses. UGT1A3 43.9 (18.9–102) Lithocholic acid 69.8 UGT1A4 391 (253–603) Hecogenin 3.99 UGT1A6UGTs 0.758Sauchinone (0.383–1.50) Well-Known 1-Naphthol Inhibitor 35.2 UGT1A9UGT1A1 9198.83 (517–1632) (5.40–14.5) NiflumicChrysin acid 0.75528.3 UGT2B7UGT1A3 0.27943.9 (0.224–0.347) (18.9–102) Lithocholic Efavirenz acid 75.469.8 UGT1A4 391 (253–603) Hecogenin 3.99 2.2. Ki of Sauchinone on UGT1A6UGT1A6 and 0.758 2B7-Mediated (0.383–1.50) Glucuronidation 1-Naphthol Activities 35.2 UGT1A9 919 (517–1632) Niflumic acid 0.755 Based on estimatedUGT2B7 IC50 values 0.279 of(0.224–0.347) sauchinone, enzymeEfavirenz kinetic75.4 assays of sauchinone on inhibition of UGT1A6 and 2B7 activities were
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