Inhibition of 20-hydroxyeicosatetraenoic acid synthesis using specific plant lignans: in vitro and human studies.
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.
School of Medicine and Pharmacology, Royal Perth Hospital, University of Western Australia, Perth, Western Australia, Australia. jwu@meddent.uwa.edu.au
Jason H Y
JH
Wu
Jonathan M
JM
Hodgson
Michael W
MW
Clarke
Adeline P
AP
Indrawan
Anne E
AE
Barden
Ian B
IB
Puddey
Kevin D
KD
Croft
D000959:Antihypertensive Agents / Q000008:administration & dosage; D019587:Dietary Supplements; D004149:Dioxoles / Q000008:administration & dosage*; D005260:Female; D006801:Humans; D006893:Hydroxyeicosatetraenoic Acids / Q000378:metabolism* / Q000652:urine; D006973:Hypertension / Q000188:drug therapy*; D066298:In Vitro Techniques; D017705:Lignans / Q000008:administration & dosage* / Q000378:metabolism; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism*; D008875:Middle Aged; D010936:Plant Extracts; D011336:Probability; D012016:Reference Values; D016896:Treatment Outcome
D000959:Antihypertensive Agents; D004149:Dioxoles; D006893:Hydroxyeicosatetraenoic Acids; D017705:Lignans; D010936:Plant Extracts; C055987:20-hydroxy-5,8,11,14-eicosatetraenoic acid; C054125:sesamin