Nonsteroid drug selectivities for cyclo-oxygenase-1 rather than cyclo-oxygenase-2 are associated with human gastrointestinal toxicity:: A full in vitro analysis

被引:1281
作者
Warner, TD
Giuliano, F
Vojnovic, I
Bukasa, A
Mitchell, JA
Vane, JR
机构
[1] St Bartholomews & Royal London Sch Med & Dent, William Harvey Res Inst, London EC1M 6BQ, England
[2] Royal Brompton Hosp, Dept Crit Care Med, London SW3 6NP, England
基金
英国惠康基金;
关键词
D O I
10.1073/pnas.96.13.7563
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
The beneficial actions of nonsteroid antiinflammatory drugs (NSAID) can be associated with inhibition of cyclo-oxygenase (COX)-2 whereas their harmful side effects are associated with inhibition of COX-1. Here we report data from two related assay systems, the human whole blood assay and a modified human whole blood assay (using human A549 cells as a source of COX-2), This assay we refer to as the William Harvey Modified Assay. Our aim was to make meaningful comparisons of both classical NSAIDs and newer COX-2-selective compounds. These comparisons of the actions of >40 NSAIDs and novel COX-2-selective agents, including celecoxib, rofecoxib and diisopropyl fluorophosphate, demonstrate a distribution of compound selectivities toward COX-1 that aligns with the risk of serious gastrointestinal complications. In conclusion, this full in vitro analysis of COX-1/2 selectivities in human tissues clearly supports the theory that inhibition of COX-1 underlies the gastrointestinal toxicity of NSAIDs in man.
引用
收藏
页码:7563 / 7568
页数:6
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