Ketoconazole inhibits oxidative modification of low density lipoprotein.
Known cytochrome P450-dependent oxygenase inhibitor ketoconazole (5-50 microM) blocked the murine macrophage-mediated modification of human low density lipoprotein (LDL) as measured by production of thiobarbituric acid-reactive substance, stimulation of [125I]LDL degradation in a fresh set of macrophages and LDL electrophoretic mobility, in a dose-dependent manner with complete inhibition at 30-40 microM. When resident macrophages were incubated with LDL in the presence of metyrapone, methoxsalen and alpha-naphthaflavone at concentrations that have been shown to inhibit the cytochrome P450-dependent oxygenases, there was no change in LDL modification. Induction of benzo[alpha]pyrene hydroxylase activity in macrophages by 24 h incubation with benzo[alpha]pyrene was accompanied by a 1.5-fold increase of LDL modification which has been leveled down by ketoconazole as well as methoxsalen and alpha-naphthaflavone. Furthermore, ketoconazole effectively diminished cell-free LDL oxidation induced by iron, but not copper ions, and reduced the spontaneous and zymosan-stimulated lucigenin-amplified chemiluminescence of macrophages. The data allow us to suggest that ketoconazole inhibits LDL oxidation by acting as an iron chelator and/or inhibitor of prooxidant forms of iron-containing enzymes.
Dushkin
M I
MI
Department of Atherogenesis, Institute of General Pathology and Human Ecology, Novosibirsk, Russia.
Zenkov
N K
NK
Menshikova
E B
EB
Pivovarova
E N
EN
Lyubimov GYu
Volsky
N N
NN
D000818:Animals; D001571:Benzoflavones / Q000494:pharmacology; D001579:Benzopyrene Hydroxylase / Q000494:pharmacology; D002478:Cells, Cultured; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D006801:Humans; D007654:Ketoconazole / Q000494:pharmacology*; D008077:Lipoproteins, LDL / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008163:Luminescent Measurements; D017737:Macrophages, Peritoneal / Q000187:drug effects* / Q000378:metabolism; D008730:Methoxsalen / Q000494:pharmacology; D008797:Metyrapone / Q000494:pharmacology; D051379:Mice; D008815:Mice, Inbred Strains; D010084:Oxidation-Reduction / Q000187:drug effects
D001571:Benzoflavones; D065607:Cytochrome P-450 Enzyme Inhibitors; D008077:Lipoproteins, LDL; C011512:alpha-naphthoflavone; D003577:Cytochrome P-450 Enzyme System; D001579:Benzopyrene Hydroxylase; D007654:Ketoconazole; D008730:Methoxsalen; D008797:Metyrapone