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(Hypertension. 2009;54:1151.)
© 2009 American Heart Association, Inc.

Original Articles

Inhibition of 20-Hydroxyeicosatetraenoic Acid Synthesis Using Specific Plant Lignans

In Vitro and Human Studies

Jason H.Y. Wu; Jonathan M. Hodgson; Michael W. Clarke; Adeline P. Indrawan; Anne E. Barden; Ian B. Puddey; Kevin D. Croft

From the School of Medicine and Pharmacology (J.H.Y.W., J.M.H., A.P.I., A.E.B., I.B.P., K.D.C.) and the Department of Core Clinical Pathology and Biochemistry (M.W.C.), Royal Perth Hospital, University of Western Australia, Perth, Australia.

Correspondence to Jason H.Y. Wu, School of Medicine and Pharmacology, University of Western Australia, PO Box X2213 GPO, Perth, Western Australia 6847, Australia. E-mail jwu{at}meddent.uwa.edu.au

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 µmol/L. It was selective toward CYP4F2 (IC₅₀: 1.9 µmol/L) and had reduced activity toward CYP4A11 (IC₅₀: >150 µmol/L), as well as cytochrome P epoxygenation of arachidonic acid (IC₅₀: >50 µmol/L). In a randomized, controlled crossover trial, overweight men and women (n=33) consumed 25 g/d of sesame (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.

Key Words: 20-HETE • cytochrome P450 • sesame • vitamin E • cardiovascular disease