Inhibition of lipoxygenases and cyclooxygenases by linoleyl hydroxamic acid: comparative in vitro studies.
In this first comparative in vitro study, linoleyl hydroxamic acid (LHA), a simple and stable derivative of linoleic acid, was tested as an inhibitor of several enzymes involved in arachidonic acid metabolism in mammals. The tested enzymes were human recombinant 5-lipoxygenase (h5-LO), porcine leukocyte 12-LO, rabbit reticulocyte 15-LO, ovine cyclooxygenases 1/2 (COX1/COX2), and human microsomal prostaglandin E synthase-1 (mPGES-1). Potato tuber and soybean lipoxygenases (ptLOX and sLOX, respectively) were studied for comparative purposes. LHA inhibited most of the tested enzymes with the exception of mPGES-1. The LHA inhibitory activity increased as follows: mPGES-1 (no inhibition)<<COX1 = COX2<h5-LO = sLOX = ptLOX<12-LO<<15-LO. The IC(50) values for COX1/COX2, h5-LO, 12-LO, and 15-LO were 60, 7, 0.6, and 0.02 muM, respectively. sLOX was the only tested enzyme that was capable of aerobic oxygenation of LHA, producing 13-hydroperoxy-LHA. The enzyme rapidly inactivated during the reaction. Therefore, LHA could be used as an effective LO/LOX inhibitor without affecting COX1/COX2 and mPGES-1. Possible implications of this observation include treating diseases and pathological states that are caused by (or lead to) hyperproduction of LO-derived metabolites, e.g., inflammation, cardiovascular disorders, cancer, asthma, allergies, psoriasis, and stroke.
Butovich
Igor A
IA
Department of Ophthalmology and Graduate School of Biomedical Sciences, University of Texas Southwestern Medical Center, Dallas, TX, USA. igor.butovich@utsouthwestern.edu
Lukyanova
Svetlana M
SM
D000818:Animals; D002851:Chromatography, High Pressure Liquid; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology*; D006801:Humans; D066298:In Vitro Techniques; D008041:Linoleic Acids / Q000494:pharmacology*; D016859:Lipoxygenase Inhibitors / Q000494:pharmacology*; D021241:Spectrometry, Mass, Electrospray Ionization
D016861:Cyclooxygenase Inhibitors; D008041:Linoleic Acids; D016859:Lipoxygenase Inhibitors; C089594:linoleic acid hydroxamate