RT Journal Article
SR Electronic
T1 Differential Inhibition of Murine Prostaglandin Synthase-1 and -2 by Nonsteroidal Anti-Inflammatory Drugs Using Exogenous and Endogenous Sources of Arachidonic Acid
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 606
OP 613
VO 280
IS 2
A1 Patricia C. Chulada
A1 Robert Langenbach
YR 1997
UL http://jpet.aspetjournals.org/content/280/2/606.abstract
AB Mouse embryonic fibroblasts (10T1/2) and Chinese hamster ovary (AS52) cell lines that stably express murine prostaglandin G/H synthase (PGHS)-1 or -2 were used to compare the effects of exogenous and endogenous arachidonic acid (AA) on isozyme-selective inhibition by acetylsalicylic acid, indomethacin, and N-[2-cyclohexyloxyl-4-nitrophenyl] methanesulfonamide (NS-398). The rationale for developing in vitro systems that identify PGHS-2-selective inhibitors is the belief that inhibition of this isoform accounts for the therapeutic benefits of nonsteroidal anti-inflammatory drugs (NSAIDs). Conversely, inhibition of PGHS-1 is believed to cause the toxic effects of NSAIDs, such as gastric and renal damage. When exogenous AA was used, acetylsalicylic acid was a 5- to 10-fold more potent inhibitor of PGHS-1, whereas indomethacin was a 4- to 5-fold more potent inhibitor of PGHS-2. Within the dose range tested (1 × 10−6 μM to 100 μM), NS-398 was highly selective for PGHS-2. When calcium ionophore A23187 was used to mobilize endogenous AA, acetylsalicylic acid and indomethacin equipotently inhibited both PGHS-1 and PGHS-2 isozymes. NS-398 remained highly selective for PGHS-2 in 10T1/2 and AS52 cells but also effectively (100%) inhibited PGHS-1 in AS52 cells. Pharmacological data derived using endogenous AA correlated better with the anti-inflammatory efficacy of these NSAIDs in laboratory animals and with the therapeutic/toxic activities of these NSAIDs in rheumatoid arthritic patients. Therefore, screening for PGHS-selective NSAIDs may best be conducted in intact cells that express high levels of each isozyme using endogenous sources of AA. The American Society for Pharmacology and Experimental Therapeutics