γ-tocopherol and its major metabolite, in contrast to α-tocopherol, inhibit cyclooxygenase activity in macrophages and epithelial cells
γ-tocopherol and its major metabolite, in contrast to α-tocopherol, inhibit cyclooxygenase activity in macrophages and epithelial cells
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DOI：
10.1073/pnas.200357097
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发表时间：
2000-10-10
影响因子：
11.1
通讯作者：
Ames, BN
中科院分区：
文献类型：
--
作者：
Jiang, Q;Elson-Schwab, I;Ames, BN
环氧合酶-2（考克斯-2）催化的前列腺素E1（PGE（2））的合成在炎症及其相关疾病如癌症和血管性心脏病中起关键作用。在这里，我们报告了γ-生育酚（γ T）在脂多糖（LPS）刺激的RAW 264，7巨噬细胞和IL-1 β处理的A549人上皮细胞中减少PGE（2）的合成，表观IC 50分别为7.5和4 μ M。饮食中γ-T的主要代谢物2，7，8-三甲基-2-（β-羧乙基）-6-羟基苯并二氢吡喃（γ-CEHC）也表现出抑制作用，在这些细胞中的IC 50约为30 μ M。相比之下，50 μ M的α-生育酚略微降低（25%）巨噬细胞中PGE（2）的形成，但对上皮细胞没有影响。γ-T和γ-CEHC的抑制作用源于其对考克斯-2活性的抑制，而不是影响蛋白质表达或底物可用性，并且似乎与抗氧化活性无关。当暴露于考克斯-2预诱导的细胞中1小时，然后加入花生四烯酸（AA）时，γ-CEHC也抑制PGE（2）的合成，而在类似的条件下，γ-T需要8- 24小时的孵育期才能引起抑制。γ-T和γ-CEHC的抑制效力随着AA浓度的增加而减弱，这表明它们可能在考克斯-2的活性位点与AA竞争。我们还观察到γ-T在脂多糖处理的巨噬细胞中适度减少亚硝酸盐积累和抑制诱导型一氧化氮合酶表达，这些研究结果表明，γ T及其主要代谢产物具有抗炎活性，生理浓度的γ T可能对人类疾病预防很重要。
Cyclooxygenase-2 (COX-2)-catalyzed synthesis of prostaglandin El (PGE(2)) plays a key role in inflammation and its associated diseases, such as cancer and vascular heart disease. Here we report that gamma-tocopherol (gamma T) reduced PGE(2) synthesis in both lipopolysaccharide (LPS)-stimulated RAW264,7 macrophages and IL-1 beta-treated A549 human epithelial cells with an apparent IC50 of 7.5 and 4 mu M, respectively. The major metabolite of dietary gamma T, 2,7,8-trimethyl-2-(beta-carboxyethyl)-6-hydroxychroman (gamma-CEHC), also exhibited an inhibitory effect, with an IC50 of approximate to 30 mu M in these cells. In contrast, alpha-tocopherol at 50 mu M slightly reduced (25%) PGE(2) formation in macrophages, but had no effect in epithelial cells. The inhibitory effects of gamma T and gamma-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. gamma-CEHC also inhibited PGE(2) synthesis when exposed for 1 h to COX-2-preinduced cells followed by the addition of arachidonic acid (AA), whereas under similar conditions, gamma T required an 8- to 24-h incubation period to cause the inhibition. The inhibitory potency of gamma T and gamma-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 gamma T in lipopolysaccharide-treated macrophages, These findings indicate that gamma T and its major metabolite possess anti-inflammatory activity and that gamma T at physiological concentrations may be important in human disease prevention.