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Ketoconazole inhibits oxidative modification of low density lipoprotein

M I Dushkin1, N K Zenkov, E B Menshikova

  • 1Department of Atherogenesis, Institute of General Pathology and Human Ecology, Novosibirsk, Russia.

Atherosclerosis
|April 7, 1995
PubMed

Insights

Ketoconazole inhibits low-density lipoprotein (LDL) oxidation by macrophages, potentially by chelating iron. This finding suggests a novel mechanism for managing LDL oxidation and its associated health risks.

Area of Science:

  • Biochemistry
  • Immunology
  • Cardiovascular Research

Background:

  • Macrophage-mediated modification of low-density lipoprotein (LDL) contributes to atherosclerosis.
  • Cytochrome P450 enzymes are implicated in LDL oxidation processes.

Purpose of the Study:

  • To investigate the effect of ketoconazole, a known cytochrome P450 inhibitor, on macrophage-mediated LDL modification.
  • To elucidate the mechanism by which ketoconazole influences LDL oxidation.

Main Methods:

  • Assessed LDL modification by measuring thiobarbituric acid-reactive substance production, [125I]LDL degradation, and electrophoretic mobility.
  • Utilized inhibitors of cytochrome P450-dependent oxygenases (metyrapone, methoxsalen, alpha-naphthaflavone).
  • Investigated cell-free LDL oxidation induced by iron and copper ions, and macrophage chemiluminescence.

Main Results:

  • Ketoconazole dose-dependently inhibited macrophage-mediated LDL modification.
  • Other P450 inhibitors did not affect LDL modification, suggesting a non-P450 mechanism for ketoconazole.
  • Ketoconazole inhibited iron-induced, but not copper-induced, LDL oxidation.
  • Ketoconazole reduced macrophage chemiluminescence.

Conclusions:

  • Ketoconazole inhibits LDL oxidation through mechanisms independent of cytochrome P450 inhibition.
  • Ketoconazole likely acts as an iron chelator or inhibits prooxidant iron-containing enzymes.
  • These findings suggest a potential therapeutic role for ketoconazole in managing LDL oxidation.

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