Background: Vitamin E isomers may protect against atherosclerosis. The aim of this study was to compare the effects of supplementation with either ␣-tocopherol (␣T) or mixed tocopherols rich in ␥-tocopherol (␥T) on markers of oxidative stress and inflammation in patients with type 2 diabetes. Methods: In a double-blind, placebo-controlled trial, 55 patients with type 2 diabetes were randomly assigned to receive (500 mg/day) (a) ␣T, (b) mixed tocopherols, or (c) placebo for 6 weeks. Cellular tocopherols, plasma and urine F 2 -isoprostanes, erythrocyte antioxidant enzyme activities, plasma inflammatory markers, and ex vivo assessment of eicosanoid synthesis were analyzed preand postsupplementation. Results: Neutrophil ␣T and ␥T increased (both P <0.001) with mixed tocopherol supplementation, whereas ␣T (P <0.001) increased and ␥T decreased (P <0.005) after ␣T supplementation. Both ␣T and mixed tocopherol supplementation resulted in reduced plasma F 2 -isoprostanes (P <0.001 and P ؍ 0.001, respectively) but did not affect 24-h urinary F 2 -isoprostanes or erythrocyte antioxidant enzyme activities. Neither ␣T nor mixed tocopherol supplementation affected plasma C-reactive protein, interleukin 6, tumor necrosis factor-␣, or monocyte chemoattractant protein-1. Stimulated neutrophil leukotriene B 4 production decreased significantly in the mixed tocoph-
Abstract-Sesamin, the major lignan found in sesame, has been shown to increase vitamin E levels by inhibiting its metabolism via the cytochrome P 450 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 IC 50 Ͻ20 mol/L. It was selective toward CYP4F2 (IC 50 : 1.9 mol/L) and had reduced activity toward CYP4A11 (IC 50 : Ͼ150 mol/L), as well as cytochrome P epoxygenation of arachidonic acid (IC 50 : Ͼ50 mol/L). In a randomized, controlled crossover trial, overweight men and women (nϭ33) Key Words: 20-HETE Ⅲ cytochrome P450 Ⅲ sesame Ⅲ vitamin E Ⅲ cardiovascular disease T he mono-oxygenation of arachidonic acid by cytochrome P 450 enzymes is recognized as an important metabolic pathway. 1 The major products generated via this enzymatic conversion include 20-hydroxyeicosatetraenoic acid (20-HETE) and regioisomeric forms of epoxyeicosatrienoic acids (EETs). 2 These arachidonic acid metabolites possess physiological functions that may influence the development of kidney diseases and hypertension. 2 20-HETE, formed via -hydroxylation of arachidonic acid, has been a focus of recent investigations that suggest that it plays a key role in the regulation of vascular and renal function. 20-HETE acts as a vasoconstrictor in renal, cerebral, and mesenteric arteries. 3 Furthermore, it has been suggested to mediate pressure natriuresis by inhibiting sodium reabsorption in the renal proximal tubule. 3 20-HETE, thus, possesses activities that could be prohypertensive or antihypertensive depending on its site of production, and this has been supported by animal models of hypertension. 4,5 Sesame seeds are a popular and commonly consumed food. 6 The abundance of unique lignans in sesame seeds has been suggested to contribute to health benefits. The predominant lignan in sesame is sesamin (Figure 1). One biological activity of sesamin that has been the target of several recent investigations is its ability to modulate ␥-tocopherol metabolism. ␥-Tocopherol is a major dietary isoform of vitamin E, and human intervention studies have demonstrated that a higher dietary intake of sesame (as seeds or oil) leads to elevated serum ␥-tocopherol concentrations. 6,7 In humans, a major pathway of ␥-tocopherol metabolism is via conversion to carboxyethyl hydroxychromans (CEHCs), which are water soluble metabolites excreted in the urine. 8 This metabolic pathway is initiated by the -hydroxylation of ␥-tocopherol by cytochrome P (C...
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