Identification and characterization of a novel delta6/delta5 fatty acid desaturase inhibitor as a potential anti-inflammatory agent.
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 delta5 and/or the delta6 fatty acid desaturase. High-throughput radioassays were developed for quantifying delta5, delta6, and delta9 desaturase activities in vitro and in vivo. CP-24879 (p-isopentoxyaniline), an aniline derivative, was identified as a mixed delta5/delta6 desaturase inhibitor during the screening of chemical and natural product 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 C4 (LTC4). Production of LTC4 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 delta5/delta6 desaturase activities were inhibited approximately 80% and AA was depleted nearly 50%. These results suggest that delta5 and/or delta6 desaturase inhibitors have the potential to manifest an anti-inflammatory response by decreasing the level of AA and the ensuing production of eicosanoids.
Obukowicz
M G
MG
Discovery Pharmacology, G.D. Searle, St. Louis, MO 63198, USA. Mark.G.Obukowicz@monsanto.com
Raz
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Pyla
P D
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Rico
J G
JG
Wendling
J M
JM
Needleman
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D000814:Aniline Compounds / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology*; D016718:Arachidonic Acid / Q000378:metabolism; D002478:Cells, Cultured; D004032:Diet; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology*; D044943:Fatty Acid Desaturases / Q000378:metabolism*; D005227:Fatty Acids / Q000378:metabolism; D066298:In Vitro Techniques; D007202:Indicators and Reagents; D017997:Leukotriene C4 / Q000096:biosynthesis; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D014407:Tumor Cells, Cultured
D000814:Aniline Compounds; D000894:Anti-Inflammatory Agents, Non-Steroidal; D004791:Enzyme Inhibitors; D005227:Fatty Acids; D007202:Indicators and Reagents; C112313:p-isopentoxyaniline; D016718:Arachidonic Acid; D017997:Leukotriene C4; D044943:Fatty Acid Desaturases