title: Inhibitory Effects of Aschantin on Cytochrome P450 and Uridine 5'-diphospho-glucuronosyltransferase Enzyme Activities in Human Liver Microsomes.
abstract: Aschantin is a bioactive neolignan found in Magnolia flos with antiplasmodial, Ca(2+)-antagonistic, platelet activating factor-antagonistic, and chemopreventive activities. We investigated its inhibitory effects on the activities of eight major human cytochrome P450 (CYP) and uridine 5'-diphospho-glucuronosyltransferase (UGT) enzymes of human liver microsomes to determine if mechanistic aschantin-enzyme interactions were evident. Aschantin potently inhibited CYP2C8-mediated amodiaquine N-de-ethylation, CYP2C9-mediated diclofenac 4'-hydroxylation, CYP2C19-mediated [S]-mephenytoin 4'-hydroxylation, and CYP3A4-mediated midazolam 1'-hydroxylation, with Ki values of 10.2, 3.7, 5.8, and 12.6 µM, respectively. Aschantin at 100 µM negligibly inhibited CYP1A2-mediated phenacetin O-de-ethylation, CYP2A6-mediated coumarin 7-hydroxylation, CYP2B6-mediated bupropion hydroxylation, and CYP2D6-mediated bufuralol 1'-hydroxylation. At 200 µM, it weakly inhibited UGT1A1-catalyzed SN-38 glucuronidation, UGT1A6-catalyzed N-acetylserotonin glucuronidation, and UGT1A9-catalyzed mycophenolic acid glucuronidation, with IC50 values of 131.7, 144.1, and 71.0 µM, respectively, but did not show inhibition against UGT1A3, UGT1A4, or UGT2B7 up to 200 µM. These in vitro results indicate that aschantin should be examined in terms of potential interactions with pharmacokinetic drugs in vivo. It exhibited potent mechanism-based inhibition of CYP2C8, CYP2C9, CYP2C19, and CYP3A4.
authors.affiliation: Drug Metabolism and Bioanalysis Laboratory, College of Pharmacy, The Catholic University of Korea, Bucheon 420-743, Korea. zuzutnseo@naver.com.
authors.forename: Soon-Sang
authors.initials: SS
authors.lastname: Kwon
authors.affiliation: Drug Metabolism and Bioanalysis Laboratory, College of Pharmacy, The Catholic University of Korea, Bucheon 420-743, Korea. jhyunkim@catholic.ac.kr.
authors.forename: Ju-Hyun
authors.initials: JH
authors.lastname: Kim
authors.affiliation: Drug Metabolism and Bioanalysis Laboratory, College of Pharmacy, The Catholic University of Korea, Bucheon 420-743, Korea. wjd1375@hanmail.net.
authors.forename: Hyeon-Uk
authors.initials: HU
authors.lastname: Jeong
authors.affiliation: Drug Metabolism and Bioanalysis Laboratory, College of Pharmacy, The Catholic University of Korea, Bucheon 420-743, Korea. yongyeon@catholic.ac.kr.
authors.forename: Yong Yeon
authors.initials: YY
authors.lastname: Cho
authors.affiliation: Natural Medicine Research Center, Korea Research Institute of Biology and Biotechnology, Chungbuk 363-883, Korea. seiryang@kribb.re.kr.
authors.forename: Sei-Ryang
authors.initials: SR
authors.lastname: Oh
authors.affiliation: Drug Metabolism and Bioanalysis Laboratory, College of Pharmacy, The Catholic University of Korea, Bucheon 420-743, Korea. sianalee@catholic.ac.kr.
authors.forename: Hye Suk
authors.initials: HS
authors.lastname: Lee
mesh_terms: D052117:Benzodioxoles / Q000494:pharmacology*; D065607:Cytochrome P-450 Enzyme Inhibitors / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D014453:Glucuronosyltransferase / Q000037:antagonists & inhibitors*; D006801:Humans; D017705:Lignans / Q000494:pharmacology*; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology*; D013997:Time Factors
chemical_list: D052117:Benzodioxoles; D065607:Cytochrome P-450 Enzyme Inhibitors; D004791:Enzyme Inhibitors; D017705:Lignans; C550309:aschantin; D014453:Glucuronosyltransferase
keywords: UDP-glucuronosyltransferase; aschantin; drug interaction; human liver microsomes; time-dependent cytochrome P450 inhibition