γ-Tocopherol and its major metabolite, in contrast to α-tocopherol, inhibit cyclooxygenase activity in macrophages and epithelial cells

Abstract

Cyclooxygenase-2 (COX-2)-catalyzed synthesis of prostaglandin E 2 (PGE2) plays a key role in inflammation and its associated diseases, such as cancer and vascular heart disease. Here we report that ␥-tocopherol (␥T) reduced PGE2 synthesis in both lipopolysaccharide (LPS)-stimulated RAW264.7 macrophages and IL-1␤-treated A549 human epithelial cells with an apparent IC 50 of 7.5 and 4 M, respectively. The major metabolite of dietary ␥T, 2,7,8-trimethyl-2-(␤-carboxyethyl)-6-hydroxychroman (␥-CEHC), also exhibited an inhibitory effect, with an IC 50 of Ϸ30 M in these cells. In contrast, ␣-tocopherol at 50 M slightly reduced (25%) PGE 2 formation in macrophages, but had no effect in epithelial cells. The inhibitory effects of ␥T and ␥-CEHC stemmed from their inhibition of COX-2 activity, rather than affecting protein expression or substrate availability, and appeared to be independent of antioxidant activity. ␥-CEHC also inhibited PGE2 synthesis when exposed for 1 h to COX-2-preinduced cells followed by the addition of arachidonic acid (AA), whereas under similar conditions, ␥T required an 8-to 24-h incubation period to cause the inhibition. The inhibitory potency of ␥T and ␥-CEHC was diminished by an increase in AA concentration, suggesting that they might compete with AA at the active site of COX-2. We also observed a moderate reduction of nitrite accumulation and suppression of inducible nitric oxide synthase expression by ␥T in lipopolysaccharide-treated macrophages. These findings indicate that ␥T and its major metabolite possess anti-inflammatory activity and that ␥T at physiological concentrations may be important in human disease prevention.

Mechanism of transfer of NO from extracellular S -nitrosothiols into the cytosol by cell-surface protein disulfide isomerase

“…In an effort to determine the effects of membrane soluble N 2 O 3 quenchers on the csPDI-dependent RSNO inf lux, HUVECs were grown in the presence of 10 M ␣-tocopherol for 14 h. Jiang et al (18) have reported that under these conditions epithelial cells were able to accumulate Ϸ0.9 nmol of ␣-tocopherol͞10 6 cells, which translates to a membrane concentration of Ϸ5 mM. The rates of intracellular DnsHCys quenching by the extracellular introduction of 25 M BSA-NO then were compared in ␣-tocopherol-treated and control cells (Fig.…”

Nutritional and Safety Outcomes from an Open-Label Micronutrient Intervention for Pediatric Bipolar Spectrum Disorders

“…a-TC reduces both prostaglandin-E2 production by macrophages and pro-inflammatory cytokine synthesis and secretion by activated macrophages and monocytes (Capuron et al 2009). c-TC also reduces prostaglandin E2 synthesis by even greater inhibition in cyclooxygenase (COX)-2 activity in macrophages, as well as reducing COX-2 activity in epithelial cells ( Jiang et al 2000). Safety data and dosing for vitamin E is as yet unclear for different human populations.…”

γ-Tocopherol or combinations of vitamin E forms induce cell death in human prostate cancer cells by interrupting sphingolipid synthesis

“…All of the subsequent experiments were performed in the presence of 1% FBS unless otherwise indicated. Because cyclooxygenase and lipoxygenase are believed to promote tumorigenesis (24-26), we decided to investigate whether the antiproliferation effect of ␥T is due to its inhibition of these enzymes (7,8). Although the presence of low micromolar concentrations of AA and LA, the substrates of cyclooxygenase and lipoxygenase, partially reversed the inhibitory effect of ␥T (Fig.…”

“…Recently, studies by us and others have indicated that other forms of vitamin E appear to have unique properties that are not shared by ␣T but may be important to human health (6). For instance, ␥T, the major form of vitamin E in U.S. diets, but not ␣T, exhibits anti-inflammatory activities by inhibiting cyclooxygenasecatalyzed prostaglandin E 2 formation in cell cultures and animals (7,8). ␥T, unlike ␣T, is strongly nucleophilic and thus is more efficient than ␣T in trapping reactive nitrogen species (9)(10)(11).…”