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

Igor A. Butovich, Svetlana M. Lukyanova

Research output: Contribution to journalArticle

13 Citations (Scopus)

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 languageEnglish (US)
Pages (from-to)1284-1294
Number of pages11
JournalJournal of Lipid Research
Volume49
Issue number6
DOIs
StatePublished - Jun 1 2008

Fingerprint

Lipoxygenases
Prostaglandin-Endoperoxide Synthases
Prostaglandins E
Arachidonate 5-Lipoxygenase
Enzymes
Allergies
Cyclooxygenase 1
Mammals
Oxygenation
Reticulocytes
Enzyme Inhibitors
Linoleic Acid
Cyclooxygenase 2
Solanum tuberosum
Metabolites
Soybeans
Psoriasis
Arachidonic Acid
Metabolism
Inhibitory Concentration 50

Keywords

  • Animal
  • Anti-cancer
  • Anti-inflammatory
  • Arachidonic acid
  • Drug discovery
  • Enzyme inhibition
  • Human
  • Linoleic acid

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Endocrinology

Cite this

Inhibition of lipoxygenases and cyclooxygenases by linoleyl hydroxamic acid : Comparative in vitro studies. / Butovich, Igor A.; Lukyanova, Svetlana M.

In: Journal of Lipid Research, Vol. 49, No. 6, 01.06.2008, p. 1284-1294.

Research output: Contribution to journalArticle

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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 = COX250 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.",
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