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 = 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.
Original language | English (US) |
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Pages (from-to) | 1284-1294 |
Number of pages | 11 |
Journal | Journal of lipid research |
Volume | 49 |
Issue number | 6 |
DOIs | |
State | Published - Jun 1 2008 |
Keywords
- Animal
- Anti-cancer
- Anti-inflammatory
- Arachidonic acid
- Drug discovery
- Enzyme inhibition
- Human
- Linoleic acid
ASJC Scopus subject areas
- Biochemistry
- Endocrinology
- Cell Biology