title: Comparison of metabolism of sesamin and episesamin by drug-metabolizing enzymes in human liver.
abstract: Sesamin and episesamin are two epimeric lignans that are found in refined sesame oil. Commercially available sesamin supplements contain both sesamin and episesamin at an approximate 1:1 ratio. Our previous study clarified the sequential metabolism of sesamin by cytochrome P450 (P450) and UDP-glucuronosyltransferase in human liver. In addition, we revealed that sesamin caused a mechanism-based inhibition (MBI) of CYP2C9, the P450 enzyme responsible for sesamin monocatecholization. In the present study, we compared the metabolism and the MBI of episesamin with those of sesamin. Episesamin was first metabolized to the two epimers of monocatechol, S- and R-monocatechols in human liver microsomes. The P450 enzymes responsible for S- and R-monocatechol formation were CYP2C9 and CYP1A2, respectively. The contribution of CYP2C9 was much larger than that of CYP1A2 in sesamin metabolism, whereas the contribution of CYP2C9 was almost equal to that of CYP1A2 in episesamin metabolism. Docking of episesamin to the active site of CYP1A2 explained the stereoselectivity in CYP1A2-dependent episesamin monocatecholization. Similar to sesamin, the episesamin S- and R-monocatechols were further metabolized to dicatechol, glucuronide, and methylate metabolites in human liver; however, the contribution of each reaction was significantly different between sesamin and episesamin. The liver microsomes from CYP2C19 ultra-rapid metabolizers showed a significant amount of episesamin dicatechol. In this study, we have revealed significantly different metabolism by P450, UDP-glucuronosyltransferase, and catechol-O-methyltransferase for sesamin and episesamin, resulting in different biological effects.
authors: Department of Biotechnology, Faculty of Engineering, Toyama Prefectural University, Imizu, Toyama, Japan.
authors: Kaori
authors: K
authors: Yasuda
authors: Shinichi
authors: S
authors: Ikushiro
authors: Shuto
authors: S
authors: Wakayama
authors: Toshimasa
authors: T
authors: Itoh
authors: Keiko
authors: K
authors: Yamamoto
authors: Masaki
authors: M
authors: Kamakura
authors: Eiji
authors: E
authors: Munetsuna
authors: Miho
authors: M
authors: Ohta
authors: Toshiyuki
authors: T
authors: Sakaki
mesh_terms: D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism*; D001711:Biotransformation; D002394:Catechol O-Methyltransferase / Q000378:metabolism*; D019388:Cytochrome P-450 CYP1A2 / Q000378:metabolism; D065731:Cytochrome P-450 CYP2C19; D065729:Cytochrome P-450 CYP2C9; D004149:Dioxoles / Q000737:chemistry / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D014453:Glucuronosyltransferase / Q000378:metabolism*; D006801:Humans; D007700:Kinetics; D017705:Lignans / Q000737:chemistry / Q000378:metabolism*; D008099:Liver / Q000187:drug effects / Q000201:enzymology*; D008297:Male; D008862:Microsomes, Liver / Q000201:enzymology; D062105:Molecular Docking Simulation; D015394:Molecular Structure; D011487:Protein Conformation; D051381:Rats; D017207:Rats, Sprague-Dawley; D011994:Recombinant Proteins / Q000378:metabolism; D013379:Substrate Specificity
chemical_list: D004149:Dioxoles; D004791:Enzyme Inhibitors; D017705:Lignans; D011994:Recombinant Proteins; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases; C504573:CYP1A2 protein, human; C045793:CYP2C19 protein, human; D019388:Cytochrome P-450 CYP1A2; D065731:Cytochrome P-450 CYP2C19; D002394:Catechol O-Methyltransferase; D014453:Glucuronosyltransferase; C054125:sesamin