Modulation of arachidonic acid metabolism by curcumin and related β-diketone derivatives:: effects on cytosolic phospholipase A2, cyclooxygenases and 5-lipoxygenase
Modulation of arachidonic acid metabolism by curcumin and related β-diketone derivatives:: effects on cytosolic phospholipase A2, cyclooxygenases and 5-lipoxygenase
复制标题
DOI：
10.1093/carcin/bgh165
复制
发表时间：
2004-09-01
期刊：
影响因子：
4.7
通讯作者：
Yang, CS
中科院分区：
文献类型：
--
作者：
Hong, JI;Bose, M;Yang, CS
花生四烯酸代谢异常参与炎症和致癌过程。在这项研究中，我们研究了天然存在的化学预防药物姜黄素及其相关的β-二酮衍生物对小鼠巨噬细胞RAW264.7细胞及其代谢产物花生四烯酸及其代谢产物在人结肠癌HT-29细胞中释放的影响。我们还检测了它们对相关酶：胞浆磷脂酶A(2)(CPLA(2))、环氧合酶(COX)以及5-脂氧合酶(5-LOX)的催化活性和蛋白水平的影响。10um时，二苯甲酰甲烷(DBM)、三甲氧基二苯甲酰甲烷(TDM)、四氢姜黄素(THC)和姜黄素能有效地抑制脂多糖(LPS)刺激的原始细胞和A23187刺激的HT-29细胞花生四烯酸及其代谢产物的释放。抑制CPLA(2)的磷酸化，这一酶的激活过程，而不是直接抑制CPLA(2)的活性似乎参与了姜黄素的作用。所有姜黄素类化合物(10um)均能有效抑制脂多糖刺激的RAW细胞前列腺素E-2(PGE(2))的生成。姜黄素(20um)可显著抑制脂多糖诱导的COX-2的表达，而不是COX的催化抑制，这可能是导致PGE(2)生成减少的原因之一。然而，在没有内毒素刺激的情况下，姜黄素增加了巨噬细胞中COX-2的水平。对分离的绵羊COX-1和COX-2酶的研究表明，姜黄素类化合物对COX-1过氧化物酶活性的抑制作用显著高于COX-2。姜黄素和THC能有效抑制重组人5-LOX的活性，其IC50值分别为0.7和3微米。结果提示，姜黄素通过阻断CPLA(2)的磷酸化，降低COX-2的表达，抑制5-LOX的催化活性，从而影响花生四烯酸代谢。这些活性可能与姜黄素及其类似物的抗炎和抗癌作用有关。
Aberrant arachidonic acid metabolism is involved in the inflammatory and carcinogenic processes. In this study, we investigated the effects of curcumin, a naturally occurring chemopreventive agent, and related beta-diketone derivatives on the release of arachidonic acid and its metabolites in the murine macrophage RAW264.7 cells and in HT-29 human colon cancer cells. We also examined their effects on the catalytic activities and protein levels of related enzymes: cytosolic phospholipase A(2) (cPLA(2)), cyclooxygenases (COX) as well as 5-lipoxygenase (5-LOX). At 10 muM, dibenzoylmethane (DBM), trimethoxydibenzoylmethane (TDM), tetrahydrocurcumin (THC) and curcumin effectively inhibited the release of arachidonic acid and its metabolites in lipopolysaccharide (LPS)-stimulated RAW cells and A23187-stimulated HT-29 cells. Inhibition of phosphorylation of cPLA(2), the activation process of this enzyme, rather than direct inhibition of cPLA(2) activity appears to be involved in the effect of curcumin. All the curcuminoids (10 muM) potently inhibited the formation of prostaglandin E-2 (PGE(2)) in LPS-stimulated RAW cells. Curcumin (20 muM) significantly inhibited LPS-induced COX-2 expression; this effect, rather than the catalytic inhibition of COX, may contribute to the decreased PGE(2) formation. Without LPS-stimulation, however, curcumin increased the COX-2 level in the macrophage cells. Studies with isolated ovine COX-1 and COX-2 enzymes showed that the curcuminoids had significantly higher inhibitory effects on the peroxidase activity of COX-1 than that of COX-2. Curcumin and THC potently inhibited the activity of human recombinant 5-LOX, showing estimated IC50 values of 0.7 and 3 muM, respectively. The results suggest that curcumin affects arachidonic acid metabolism by blocking the phosphorylation of cPLA(2), decreasing the expression of COX-2 and inhibiting the catalytic activities of 5-LOX. These activities may contribute to the anti-inflammatory and anticarcinogenic actions of curcumin and its analogs.