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

Abstract

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 5 COX2,h5-LO 5 sLOX 5 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 mM, 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, I. A., and S. M. Lukyanova. Inhibition of lipoxygenases and cyclooxygenases by linoleyl hydroxamic acid: comparative in vitro studies.

Identification of toxic fatty acid amides isolated from the harmful alga Prymnesium parvum carter

“…Inhibition of potato lipoxygenase is through the possible formation of an Fe 3+ :LHA complex (Butovich and Reddy, 2002). The IC 50 values of LHA are over 3 orders of magnitude lower for certain lipoxygenases than cycloxygenases (Butovich and Lukyanova, 2008). Metal containing organic toxins have also been characterized and reported in the dinoflagellate, Pfeisteria piscicida (Moeller et al, 2007).…”

“…(Z,Z)-N-Hydroxy-9,12-octadecadienamide, linoleyl hydroxamic acid (LHA) displays biological activity as an inhibitor of lipoxygenases and cyclooxygenases, which are important enzymes in fatty acid metabolism and whose disruption is associated with several pathological states (Butovich and Reddy, 2002;Butovich and Lukyanova, 2008). Inhibition of potato lipoxygenase is through the possible formation of an Fe 3+ :LHA complex (Butovich and Reddy, 2002).…”

Lipoxygenase regulation in vivo and in vitro by lipid compounds

“…The differences in the PL effects on the enzymes from plant and animal sources can be explained comparing the affi nity of these enzymes to diversely charged phospholipids, which translocate to the mem- [50][51][52] brane through the same mechanism [19,24]. Affi nity to a particular lipid is associated with the enzyme localization in the cell.…”

“…Another N-containing derivative of PUFAs is linoleyl hydroxamic acid (LHA). LHA was shown to be an inhibitor for pt5-LO [50], soybean 15-LO [52,60], porcine leucocytes 12-LO [51], rabbit reticulocyte 15-LO. Using the model system of mixed micelles with constant molar ratio, it was found that LHA acted as a noncompetitive inhibitor of pt5-LO.…”

Syntheses and transformations of alicyclic β-aminohydroxamic acids

“…Linoleyl hydroxamic acid, studied as lipoxygenase inhibitor by Butovich and Lukyanova, was found to be effective against 15and 12-LOX. [36] Tepoxalin has been approved for the treatment of osteoarthritis in dogs. [37] Wong et al synthesized -aminohydroxamic acid derivatives, which are able to act as selective LTA 4 hydrolase inhibitors in vitro [38] (Figure 8).…”