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Journal of Lipid Research, Vol. 49, 1284-1294, June 2008
Copyright © 2008 by American Society for Biochemistry and Molecular Biology

Inhibition of lipoxygenases and cyclooxygenases by linoleyl hydroxamic acid: comparative in vitro studies^*

Igor A. Butovich¹ and Svetlana M. Lukyanova²

Department of Ophthalmology and Graduate School of Biomedical Sciences, University of Texas Southwestern Medical Center, Dallas, TX

^* The authors would like to acknowledge support from the Swedish Foundation for International Cooperation in Research and Higher Education, the National Institutes of Health (Grants 5P30AR-04194014 and EY-016664), and by an unrestricted grant from Research to Prevent Blindness, Inc. (New York, NY).

Published, JLR Papers in Press, 27 February 2008.

² Current address of S.M. Lukyanova: Alcon Laboratories, Inc., Fort Worth, TX 76134.

¹ To whom correspondence should be addressed. e-mail: igor.butovich{at}utsouthwestern.edu

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 IC₅₀ values for COX1/COX2, h5-LO, 12-LO, and 15-LO were 60, 7, 0.6, and 0.02 µM, 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.

Supplementary key words human • animal • arachidonic acid • linoleic acid • enzyme inhibition • anti-inflammatory • anti-cancer • drug discovery

Abbreviations: AA, arachidonic acid (eicosatetra-5Z,8Z,11Z,14Z-enoic acid); APCI, atmospheric pressure chemical ionization; au, arbitrary unit (unitless); COX1/2, ovine cyclooxygenases 1 and 2; 1D, one-dimensional; DAD, diode array detector; HETE, hydroxyeicosatetraenoic acid; ESI-MS, electrospray ionization mass spectrometry; HPETE, hydroperoxyeicosatetraenoic acid; HPODE, hydroperoxyoctadecadienoic acid; h5-LO, human recombinant 5-lipoxygenase; LA, linoleic acid (octadeca-9Z,12Z-dienoic acid); LHA, linoleyl hydroxamic acid; LO, lipoxygenase (mammalian); LOX, lipoxidase (plant); mPGES-1, human microsomal prostaglandin E synthase-1; NP-HPLC, normal-phase HPLC; NSAID, nonsteroidal anti-inflammatory drug; ptLOX, potato tuber lipoxygenase (lipoxidase); RP-HPLC, reverse-phase HPLC; sLOX, soybean lipoxygenase (lipoxidase)

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