Inhibition of 20-hydroxyeicosatetraenoic acid synthesis using specific plant lignans: in vitro and human studies.

Abstract

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.

• Authors: Jason H Y Wu, Jonathan M Hodgson, Michael W Clarke, Adeline P Indrawan, Anne E Barden, Ian B Puddey, Kevin D Croft
• Journal: Hypertension (Dallas, Tex. : 1979) (Hypertension) Vol. 54 Issue 5 Pg. 1151-8 (Nov 2009) ISSN: 1524-4563 [Electronic] United States
• PMID: 19786646 (Publication Type: Comparative Study, Journal Article, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)

Chemical References

• Antihypertensive Agents
• Dioxoles
• Hydroxyeicosatetraenoic Acids
• Lignans
• Plant Extracts
• 20-hydroxy-5,8,11,14-eicosatetraenoic acid
• sesamin

Topics

• Antihypertensive Agents (administration & dosage)
• Dietary Supplements
• Dioxoles (administration & dosage)
• Female
• Humans
• Hydroxyeicosatetraenoic Acids (metabolism, urine)
• Hypertension (drug therapy)
• In Vitro Techniques
• Lignans (administration & dosage, metabolism)
• Male
• Microsomes, Liver (drug effects, metabolism)
• Middle Aged
• Plant Extracts
• Probability
• Reference Values
• Treatment Outcome