Department of Biotechnology, Faculty of Engineering, Toyama Prefectural University, Imizu, Toyama, Japan.
Drug Metab Dispos. 2012 Oct;40(10):1917-26. doi: 10.1124/dmd.112.045906. Epub 2012 Jun 29.
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.
芝麻素和表芝麻素是两种在精炼芝麻油中发现的差向异构体木质素。市售的芝麻素补充剂中含有约 1:1 比例的芝麻素和表芝麻素。我们之前的研究阐明了芝麻素在人肝中的细胞色素 P450（P450）和 UDP-葡糖醛酸基转移酶的顺序代谢。此外，我们还揭示了芝麻素对负责芝麻素单儿茶酚化的 P450 酶 CYP2C9 引起了基于机制的抑制（MBI）。在本研究中，我们比较了表芝麻素与芝麻素的代谢和 MBI。表芝麻素首先在人肝微粒体中代谢为单儿茶酚的两种差向异构体，S-和 R-单儿茶酚。负责 S-和 R-单儿茶酚形成的 P450 酶分别为 CYP2C9 和 CYP1A2。CYP2C9 在芝麻素代谢中的贡献远大于 CYP1A2，而 CYP2C9 在表芝麻素代谢中的贡献几乎与 CYP1A2 相等。表芝麻素与 CYP1A2 活性位点的对接解释了 CYP1A2 依赖性表芝麻素单儿茶酚化的立体选择性。与芝麻素类似，表芝麻素的 S-和 R-单儿茶酚进一步代谢为二儿茶酚、葡萄糖醛酸和甲基化代谢物在人肝中；然而，芝麻素和表芝麻素之间的每个反应的贡献有很大差异。CYP2C19 超快代谢者的肝微粒体显示出大量的表芝麻素二儿茶酚。在这项研究中，我们揭示了芝麻素和表芝麻素在 P450、UDP-葡糖醛酸基转移酶和儿茶酚-O-甲基转移酶方面的代谢有显著差异，从而产生不同的生物学效应。
