Nonredox 5-lipoxygenase inhibitors require glutathione peroxidase for efficient inhibition of 5-lipoxygenase activity

Mol Pharmacol. 1998 Aug;54(2):445-51. doi: 10.1124/mol.54.2.445.


Nonredox type 5-lipoxygenase (5-LO) inhibitors, such as ZM 230487, its methyl analogue ZD 2138, or the Merck compound L-739,010, suppress cellular leukotriene synthesis of ionophore stimulated granulocytes with IC50 values of about 50 nM. However, in cell homogenates or in preparations of purified enzyme, up to 150-fold higher concentrations are required for similar inhibition of 5-LO activity. This loss of 5-LO inhibition in cell homogenates was reversed by addition of glutathione or dithiothreitol, which increased the inhibitory potency of ZM 230487 or L-739,010 by about 100 to 150-fold so that 5-LO inhibition was comparable with that of intact cells. In the presence of thiols, addition of hydroperoxide [13(S)-HpODE], glutathione-peroxidase inhibition by iodacetate or selenium-deficiency lead to impaired 5-LO inhibition by ZM 230487 in cell homogenates. Moreover, addition of glutathione peroxidase was required for efficient inhibition of purified human 5-LO by ZM 230487. The data suggest that low hydroperoxide concentrations are important for efficient 5-LO inhibition by ZM 230487. The kinetic analysis revealed a noncompetitive inhibition of 5-LO by ZM 230487 at low hydroperoxide levels, whereas it acted as a competitive inhibitor with low affinity under nonreducing conditions in granulocyte homogenates. No such redox-dependent effects were observed with the 5-LO inhibitor BWA4C, the 5-LO activating protein-inhibitor MK-886 or the pentacyclic triterpene acetyl-11-keto-beta-boswellic acid. These data suggest that physiological conditions associated with oxidative stress and increased peroxide levels lead to impaired efficacy of nonredox type 5-LO inhibitors like ZM 230487 or L-739,010. This could explain the reported lack of activity of this class of 5-LO inhibitors in chronic inflammatory processes.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Arachidonate 5-Lipoxygenase / metabolism
  • Bridged Bicyclo Compounds / pharmacology
  • Cells, Cultured / drug effects
  • Enzyme Activation
  • Escherichia coli / genetics
  • Glutathione Peroxidase / metabolism*
  • Humans
  • Hydrogen Peroxide / metabolism
  • Hydrogen Peroxide / pharmacology
  • Lipoxygenase Inhibitors* / pharmacology*
  • Oxidation-Reduction
  • Oxidative Stress / drug effects
  • Peroxidase / antagonists & inhibitors
  • Peroxidase / metabolism
  • Pyrans / pharmacology*
  • Quinolines / pharmacology
  • Quinolones / pharmacology*
  • Selenium / metabolism
  • Sulfhydryl Compounds / metabolism
  • Sulfhydryl Compounds / pharmacology


  • Bridged Bicyclo Compounds
  • L 739010
  • Lipoxygenase Inhibitors
  • Pyrans
  • Quinolines
  • Quinolones
  • Sulfhydryl Compounds
  • ZM 230487
  • Hydrogen Peroxide
  • Peroxidase
  • Glutathione Peroxidase
  • Arachidonate 5-Lipoxygenase
  • Selenium