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Ketoconazole inhibits oxidative modification of low density lipoprotein.

Abstract：

: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.

journal_name

Atherosclerosis

journal_title

Atherosclerosis

authors

Dushkin MI,Zenkov NK,Menshikova EB,Pivovarova EN,Lyubimov GYu,Volsky NN

doi

10.1016/0021-9150(94)05456-s

subject

Has Abstract

pub_date

1995-04-07 00:00:00

pages

9-18

issue

1

eissn

0021-9150

issn

1879-1484

pii

0021-9150(94)05456-S

journal_volume

114

pub_type

杂志文章

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