花生四烯酸
药理学
化学
脂肪酸去饱和酶
脂肪酸
体内
药效学
水肿
作用机理
药代动力学
酶
生物化学
体外
生物
内科学
多不饱和脂肪酸
医学
生物技术
作者
Mark G. Obukowicz,Dean J. Welsch,W. J. Salsgiver,Cynthia L. Martin-Berger,Kevin Chinn,Kevin L. Duffin,Amiram Raz,Philip Needleman
出处
期刊:PubMed
日期:1998-10-01
卷期号:287 (1): 157-66
被引量:33
摘要
Decreased synthesis of arachidonic acid by inhibition of the Delta6 or Delta5 desaturase was evaluated as a means to mitigate inflammation. Using quantitative in vitro and in vivo radioassays, novel compounds representing five classes of Delta5 desaturase inhibitors and one class of Delta6 desaturase inhibitor were identified. The Delta6 desaturase inhibitor, SC-26196, had pharmacokinetic and pharmacodynamic profiles in mice that allowed for the evaluation of the pharmacological effects of chronic inhibition of desaturase activity. SC-26196 decreased edema to the same extent as indomethacin or essential fatty acid deficiency in the carrageenan paw edema model in the mouse. The antiinflammatory properties of SC-26196 were consistent with its mechanism of action as a Delta6 desaturase inhibitor: 1) A correlation existed between inhibition of liver Delta6 desaturase activity and decreases in edema. 2) The onset of the decrease in edema was time dependent. 3) Selective reduction of arachidonic acid occurred dose dependently in liver, plasma and peritoneal cells. 4) In the presence of SC-26196, controlled refeeding of arachidonic acid, but not oleic acid, reversed the changes resulting from desaturase inhibition. The Delta6 desaturase may be a target for development of antiinflammatory drugs whose mechanism of action is unique.
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