Wu Jason H Y, Hodgson Jonathan M, Clarke Michael W, Indrawan Adeline P, Barden Anne E, Puddey Ian B, Croft Kevin D
School of Medicine and Pharmacology, Royal Perth Hospital, University of Western Australia, Perth, Western Australia, Australia.
Hypertension. 2009 Nov;54(5):1151-8. doi: 10.1161/HYPERTENSIONAHA.109.139352. Epub 2009 Sep 28.
Sesamin, the major lignan found in sesame, has been shown to increase vitamin E levels by inhibiting its metabolism via the cytochrome P450 isozyme CYP4F2. CYP4F2 and CYP4A11 are the predominant human isoforms that synthesize 20-hydroxyeicosatetraenoic acid (20-HETE) from arachidonic acid. Considerable evidence suggests that 20-HETE may play a role in the pathogenesis of hypertension. We hypothesized that sesamin could be an inhibitor of 20-HETE synthesis. This study investigated the effects of sesamin on 20-HETE synthesis in vitro and the effect of sesame supplementation on plasma and urinary 20-HETE concentrations in humans. Human microsomes were used to investigate the potency and selectivity of sesamin inhibition of 20-HETE synthesis. Sesamin inhibited human renal and liver microsome 20-HETE synthesis with IC50 <20 micromol/L. It was selective toward CYP4F2 (IC50: 1.9 micromol/L) and had reduced activity toward CYP4A11 (IC50: >150 micromol/L), as well as cytochrome P epoxygenation of arachidonic acid (IC50: >50 micromol/L). In a randomized, controlled crossover trial, overweight men and women (n=33) consumed 25 g/d of sesame (approximately 50 mg/d of sesame lignan) or an isocaloric matched control for 5 weeks each. Relative to control, sesame supplementation resulted in a 28% decrease in plasma and a 32% decrease in urinary 20-HETE (P<0.001). Urinary sodium, potassium, and blood pressure were not affected. This study demonstrates for the first time that sesame supplementation in humans reduces the plasma and urinary levels of 20-HETE, likely via inhibition of CYP4F2 by sesame lignans. These results suggest that sesame lignans could be used for the investigation of potential roles of 20-HETE in humans.
芝麻素是芝麻中发现的主要木脂素，已被证明可通过抑制其经细胞色素P450同工酶CYP4F2的代谢来提高维生素E水平。CYP4F2和CYP4A11是从花生四烯酸合成20-羟基二十碳四烯酸（20-HETE）的主要人类同工型。大量证据表明，20-HETE可能在高血压发病机制中起作用。我们推测芝麻素可能是20-HETE合成的抑制剂。本研究调查了芝麻素对体外20-HETE合成的影响以及补充芝麻对人体血浆和尿液中20-HETE浓度的影响。使用人微粒体来研究芝麻素抑制20-HETE合成的效力和选择性。芝麻素抑制人肾和肝微粒体20-HETE合成，IC50<20微摩尔/升。它对CYP4F2具有选择性（IC50：1.9微摩尔/升），对CYP4A11的活性降低（IC50：>150微摩尔/升），以及对花生四烯酸的细胞色素P环氧化作用（IC50：>50微摩尔/升）。在一项随机对照交叉试验中，超重男性和女性（n = 33）分别连续5周每天食用25克芝麻（约50毫克/天芝麻木脂素）或等热量匹配对照物。相对于对照，补充芝麻导致血浆中20-HETE降低28%，尿液中降低32%（P<0.001）。尿钠、钾和血压未受影响。本研究首次证明，在人体中补充芝麻可降低血浆和尿液中20-HETE的水平，可能是通过芝麻木脂素抑制CYP4F2实现的。这些结果表明，芝麻木脂素可用于研究20-HETE在人体中的潜在作用。
