Identification and characterization of a novel Δ6/Δ5 fatty acid desaturase inhibitor as a potential anti-inflammatory agent
Identification and characterization of a novel Δ6/Δ5 fatty acid desaturase inhibitor as a potential anti-inflammatory agent
复制标题
DOI：
10.1016/s0006-2952(97)00665-5
复制
发表时间：
1998-04-01
影响因子：
5.8
通讯作者：
Needleman, P
中科院分区：
文献类型：
--
作者：
Obukowicz, MG;Raz, A;Needleman, P
必需脂肪酸缺乏或补充n-3多不饱和脂肪酸的抗炎特性归因于花生四烯酸含量的降低（AA; 20:4 n-6）。另一种合理的消耗AA的方法是通过选择性抑制5和/或6脂肪酸去饱和酶来减少内源性AA的合成。开发了高通量放射测定法，用于定量体外和体内Delta 5、Delta 6和Delta 9去饱和酶的活性。CP-24879 （p-isopentoxyaniline）是一种苯胺衍生物，在化学和天然农产品文库筛选过程中被鉴定为delta5 / delta6混合去饱和酶抑制剂。在长期用CP 24879培养的小鼠肥大细胞瘤ABMC-7细胞中，去饱和酶活性的抑制与AA的消耗程度和白三烯C的产生减少相关（LTC(4)）。在外源AA存在的情况下，通过刺激细胞恢复LTC(4)的产生，表明内源AA作为底物受到限制。长期给予最大耐受剂量CP-24879 （3mg /kg, t.i.d）的小鼠肝脏中，Delta 5/Delta 6去饱和酶活性被抑制约80%，AA被消耗近50%。这些结果表明，Delta 5和/或Delta 6去饱和酶抑制剂可能通过降低AA水平和随后的类二十烷酸的产生而表现出抗炎反应。(C) 1998爱思唯尔科学有限公司
The anti-inflammatory properties of essential fatty acid deficiency or n-3 polyunsaturated fatty acid supplementation have been attributed to a reduced content of arachidonic acid (AA; 20:4 n-6). An alternative, logical approach to depleting AA would be to decrease endogenous synthesis of AA by selectively inhibiting the Delta 5 and/or the Delta 6 fatty acid desaturase. High-throughput radioassays were developed for quantifying Delta 5, Delta 6, and Delta 9 desaturase activities in vitro and in vivo. CP-24879 (p-isopentoxyaniline), an aniline derivative, was identified as a mixed Delta 5/Delta 6 desaturase inhibitor during the screening of chemical and natural produce libraries. In mouse mastocytoma ABMC-7 cells cultured chronically with CP 24879, there was a concentration-dependent inhibition of desaturase activity that correlated with the degree of depletion of AA and decreased production of leukotriene C(4) (LTC(4)). Production of LTC(4) was restored by stimulating the cells in the presence of exogenous AA, indicating that endogenous AA was limiting as substrate. In the livers of mice treated chronically with the maximally tolerated dose of CP-24879 (3 mg/kg, t.i.d.), combined Delta 5/Delta 6 desaturase activities were inhibited approximately 80% and AA was depleted nearly 50%. These results suggest that Delta 5 and/or Delta 6 desaturase inhibitors have the potential to manifest an anti inflammatory response by decreasing the level of AA and the ensuing production of eicosanoids. (C) 1998 Elsevier Science Inc.