title: Characterization of Phase I and Phase II Hepatic Metabolism and Reactive Intermediates of Larrea nitida Cav. and Its Lignan Compounds.
abstract: Larrea nitida Cav. (LNC), which belongs to the family Zygophyllaceae, is widely indigenous and used in South America to treat various pathological conditions. It contains the antioxidant and antiinflammatory but toxic nordihydroguaiaretic acid (NDGA) as well as O-methylated metabolite of NDGA (MNDGA) as bioactive compounds. The hepatic metabolism-based toxicological potential of extracts of LNC (LNE), NDGA, and MNDGA has not previously been reported. The present study aimed to characterize the phase I and phase II hepatic metabolism and reactive intermediates of LNE, NDGA, and MNDGA and their effects on the major drug-metabolizing enzymes in vitro and ex vivo. A methanol extract of LNC collected from Chile as well as NDGA and MNDGA isolated from LNE were subjected to metabolic stability assays in liver microsomes in the presence of the cofactors reduced nicotinamide dinucleotide phosphate (NADPH) and/or uridine 5'-diphosphoglucuronic acid (UDPGA). Cytochrome P450 (CYP) inhibition assays were performed using CYP isozyme-specific model substrates to examine the inhibitory activities of LNE, NDGA, and MNDGA, which were expressed as % inhibition and IC50values. Ex vivo CYP induction potential was investigated in the liver microsomes prepared from the rats intraperitoneally administered with LNE. Glutathione (GSH) adduct formation was monitored by LC-MS3analysis of the microsomal incubation samples with either NDGA or MNDGA and an excess of GSH to determine the formation of electrophilic reactive intermediates. Both NDGA and MNDGA were stable to NADPH-dependent phase I metabolism, but labile to glucuronide conjugation. LNE, NDGA, and MNDGA showed significant inhibitory effects on CYP1A2, 2C9, 2D6, and/or 3A4, with IC50values in the micromolar range. LNE was found to be a CYP1A2 inducer in ex vivo rat experiments, and mono- and di-GSH adducts of both NDGA and MNDGA were identified by LC-MS3analysis. Our study suggests that hepatic clearance is the major elimination route for the lignans NDGA and MNDGA present in LNE. These lignans may possess the ability to modify biomacromolecules via producing reactive intermediates. In addition, LNE, NDGA, and MNDGA are found to be inhibitors for various CYP isozymes such as CYP2C9 and 3A4. Thus, the consumption of LNC as an herbal preparation or NDGA may cause metabolism-driven herb-drug interactions. Copyright © 2016 John Wiley & Sons, Ltd.
authors.affiliation: Graduate School of Biological Sciences, Sookmyung Women's University, 100, Chungparo 47-gil, Seoul, 140-742, Korea.
authors.forename: Hyesoo
authors.initials: H
authors.lastname: Jeong
authors.affiliation: Graduate School of Biological Sciences, Sookmyung Women's University, 100, Chungparo 47-gil, Seoul, 140-742, Korea.
authors.forename: Soolin
authors.initials: S
authors.lastname: Kim
authors.affiliation: Graduate School of Biological Sciences, Sookmyung Women's University, 100, Chungparo 47-gil, Seoul, 140-742, Korea.
authors.forename: Jimin
authors.initials: J
authors.lastname: Lee
authors.affiliation: Department of Biological Sciences, College of Science, Sookmyung Women's University, 100, Chungparo 47-gil, Seoul, 140-742, Korea.
authors.forename: Jin Young
authors.initials: JY
authors.lastname: Park
authors.affiliation: Graduate School of Biological Sciences, Sookmyung Women's University, 100, Chungparo 47-gil, Seoul, 140-742, Korea.
authors.forename: Wenmei
authors.initials: W
authors.lastname: Zhou
authors.affiliation: Graduate School of Biological Sciences, Sookmyung Women's University, 100, Chungparo 47-gil, Seoul, 140-742, Korea.
authors.forename: Xiyuan
authors.initials: X
authors.lastname: Liu
authors.affiliation: College of Pharmacy, Sookmyung Women's University, 100, Chungparo 47-gil, Seoul, 140-742, Korea.
authors.forename: So Dam
authors.initials: SD
authors.lastname: Kim
authors.affiliation: College of Pharmacy, Sookmyung Women's University, 100, Chungparo 47-gil, Seoul, 140-742, Korea.
authors.forename: Yun Seon
authors.initials: YS
authors.lastname: Song
authors.affiliation: College of Pharmacy, Sookmyung Women's University, 100, Chungparo 47-gil, Seoul, 140-742, Korea.
authors.forename: Chang-Young
authors.initials: CY
authors.lastname: Jang
authors.affiliation: Natural Medicine Research Center, Korea Research Institute of Bioscience and Biotechnology, Chungbuk, 363-883, Korea.
authors.forename: Sei-Ryang
authors.initials: SR
authors.lastname: Oh
authors.affiliation: Natural Medicine Research Center, Korea Research Institute of Bioscience and Biotechnology, Chungbuk, 363-883, Korea.
authors.forename: Sangho
authors.initials: S
authors.lastname: Choi
authors.affiliation: Department of Biological Sciences, College of Science, Sookmyung Women's University, 100, Chungparo 47-gil, Seoul, 140-742, Korea.
authors.forename: Minsun
authors.identifier: http://orcid.org/0000-0003-1274-7462
authors.initials: M
authors.lastname: Chang
mesh_terms: D000818:Animals; D005260:Female; D041743:Herb-Drug Interactions; D006801:Humans; D032442:Larrea / Q000737:chemistry*; D017705:Lignans / Q000737:chemistry* / Q000494:pharmacology; D008099:Liver / Q000378:metabolism*; D008862:Microsomes, Liver / Q000187:drug effects*; D051381:Rats
chemical_list: D017705:Lignans
keywords: Larrea nitida Cav; MDGA; NDGA; drug metabolism; drug-herb interaction; glutathione adducts