title: Metabolic characterization of meso-dihydroguaiaretic acid in liver microsomes and in mice.
abstract: meso-Dihydroguaiaretic acid (MDGA) is a major component of Myristica fragrans and Machilus thunbergii that is traditionally used as a spice and for medicinal purposes. Despite reports of various biological activities exerted by MDGA, there is no information regarding its metabolic properties. The purpose of this study was to determine the metabolic stability and cytochrome P450 (CYP) inhibitory potential of MDGA, using pooled human liver microsomes (HLMs) to characterize its metabolic properties. In addition, pharmacokinetic analysis was performed in mice treated intravenously (5 mg/kg) or orally (20 mg/kg) with MDGA for comparison with our in vitro results. The half-life of MDGA in HLMs and mouse liver microsomes incubated with NADPH, UDPGA or NADPH plus UDPGA was 25.41 and 22.74, 0.39 and 0.20 or 0.28 and 0.22 min, respectively. In our pharmacokinetic study, MDGA rapidly declined in plasma and had low bioavailability, which was attributable to extensive metabolism by UDP-glucuronosyltransferases and CYPs. Among CYP isoforms, CYP2E1 activity was selectively inhibited by MDGA through a competitive inhibitory mode, with an inhibitory constant (Ki) value of 13.1 µM. These results suggest that MDGA can be used as a selective CYP2E1 inhibitor in vitro, which warrants evaluation of the pharmacological significance of MDGA-induced CYP2E1 inhibition.
authors.affiliation: College of Pharmacy, Chungnam National University, Daejeon 305-764, Republic of Korea.
authors.forename: Jang Su
authors.initials: JS
authors.lastname: Jeon
authors.affiliation: Bio-Evaluation Center, KRIBB, Ochang, Chungbuk 363-883, Republic of Korea.
authors.forename: Soo Jin
authors.initials: SJ
authors.lastname: Oh
authors.affiliation: College of Pharmacy, Chungnam National University, Daejeon 305-764, Republic of Korea.
authors.forename: Ji-Yoon
authors.initials: JY
authors.lastname: Lee
authors.affiliation: College of Pharmacy, Chungnam National University, Daejeon 305-764, Republic of Korea.
authors.forename: Chang Seon
authors.initials: CS
authors.lastname: Ryu
authors.affiliation: College of Pharmacy, Hanyang University, Ansan, Gyeonggido 426-791, Republic of Korea.
authors.forename: Young-Mi
authors.initials: YM
authors.lastname: Kim
authors.affiliation: College of Pharmacy, Seoul National University, Gwanak-ro 1, Gwanak-gu, Seoul 151-742, Republic of Korea.
authors.forename: Byung Hoon
authors.initials: BH
authors.lastname: Lee
authors.affiliation: College of Pharmacy, Chungnam National University, Daejeon 305-764, Republic of Korea. Electronic address: sangkim@cnu.ac.kr.
authors.forename: Sang Kyum
authors.initials: SK
authors.lastname: Kim
mesh_terms: D000818:Animals; D065691:Cytochrome P-450 CYP2E1 Inhibitors / Q000097:blood / Q000493:pharmacokinetics; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D014453:Glucuronosyltransferase / Q000378:metabolism; D006139:Guaiacol / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics; D006207:Half-Life; D006801:Humans; D019770:Lauraceae / Q000737:chemistry; D017705:Lignans / Q000097:blood / Q000493:pharmacokinetics*; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D008862:Microsomes, Liver / Q000187:drug effects* / Q000378:metabolism
chemical_list: D065691:Cytochrome P-450 CYP2E1 Inhibitors; D017705:Lignans; C015816:dihydroguaiaretic acid; D006139:Guaiacol; D003577:Cytochrome P-450 Enzyme System; D014453:Glucuronosyltransferase
keywords: CYP inhibition; CYP2E1; Metabolic stability; Pharmacokinetics; meso-Dihydroguaiaretic acid