title: Metabolic interactions of magnolol with cytochrome P450 enzymes: uncompetitive inhibition of CYP1A and competitive inhibition of CYP2C.
abstract: Magnolol (MAG; 5,5'-diallyl-2,2'-biphenyldiol) is a major bioactive component of Magnolia officinalis. We investigated the metabolic interactions of MAG with hepatic cytochrome P450 monooxygenase (CYP) through in vitro microsomal metabolism study using human (HLM) and rat liver microsomes (RLM). CYP2C and 3A subfamilies were significantly involved in the metabolism of MAG, while CYP1A subfamily was not in HLM and RLM. The relative contribution of phase I enzymes including CYP to the metabolism of MAG was comparable to that of uridine diphosphate glucuronosyltransferase (UGT) in RLM. Moreover, MAG potently inhibited the metabolic activity of CYP1A (IC50 of 1.62 μM) and 2C (IC50 of 5.56 μM), while weakly CYP3A (IC50 of 35.0 μM) in HLM and RLM. By the construction of Dixon plot, the inhibition type of MAG on CYP activity in RLM was determined as follows: uncompetitive inhibitor for CYP1A (Ki of 1.09-12.0 μM); competitive inhibitor for CYP2C (Ki of 10.0-15.2 μM) and 3A (Ki of 93.7-183 μM). Based on the comparison of the current IC50 and Ki values with a previously reported liver concentration (about 13 μM) of MAG after its seven times oral administration at a dose of 50 mg/kg in rats, it is suggested that MAG could show significant inhibition of CYP1A and 2C, but not CYP3A, in the in vivo rat system. These results could lead to further studies in clinically significant metabolism-mediated MAG-drug interactions.
authors.affiliation: a College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University , Seoul , Republic of Korea .
authors.forename: Sang-Bum
authors.initials: SB
authors.lastname: Kim
authors.affiliation: b College of Pharmacy, The Catholic University of Korea , Bucheon , Republic of Korea .
authors.forename: Hee Eun
authors.initials: HE
authors.lastname: Kang
authors.affiliation: c College of Pharmacy, Kangwon National University , Chuncheon , Republic of Korea .
authors.forename: Hyun-Jong
authors.initials: HJ
authors.lastname: Cho
authors.affiliation: d Natural Products Research Institute and College of Pharmacy, Seoul National University , Seoul , Republic of Korea , and.
authors.forename: Yeong Shik
authors.initials: YS
authors.lastname: Kim
authors.affiliation: a College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University , Seoul , Republic of Korea .
authors.forename: Suk-Jae
authors.initials: SJ
authors.lastname: Chung
authors.affiliation: e College of Pharmacy and Natural Medicine Research Institute, Mokpo National University , Jeonnam , Republic of Korea.
authors.forename: In-Soo
authors.initials: IS
authors.lastname: Yoon
authors.affiliation: a College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University , Seoul , Republic of Korea .
authors.forename: Dae-Duk
authors.initials: DD
authors.lastname: Kim
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001713:Biphenyl Compounds / Q000008:administration & dosage / Q000494:pharmacology*; D019388:Cytochrome P-450 CYP1A2; D051544:Cytochrome P-450 CYP3A / Q000187:drug effects / Q000378:metabolism; D065607:Cytochrome P-450 Enzyme Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D003577:Cytochrome P-450 Enzyme System / Q000187:drug effects* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D006801:Humans; D020128:Inhibitory Concentration 50; D017705:Lignans / Q000008:administration & dosage / Q000494:pharmacology*; D031566:Magnolia / Q000737:chemistry; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D001713:Biphenyl Compounds; D065607:Cytochrome P-450 Enzyme Inhibitors; D017705:Lignans; C400322:cytochrome P-450 CYP2C subfamily; C005498:magnolol; D003577:Cytochrome P-450 Enzyme System; D019388:Cytochrome P-450 CYP1A2; D051544:Cytochrome P-450 CYP3A
keywords: Cytochrome P450; enzyme inhibition mechanism; hepatic metabolism; human liver microsome; magnolol; rat liver microsome