Dushkin M I, Zenkov N K, Menshikova E B, Pivovarova E N, Volsky N N
Department of Atherogenesis, Institute of General Pathology and Human Ecology, Novosibirsk, Russia.
Atherosclerosis. 1995 Apr 7;114(1):9-18. doi: 10.1016/0021-9150(94)05456-s.
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.
已知细胞色素P450依赖性加氧酶抑制剂酮康唑（5 - 50微摩尔）可阻断小鼠巨噬细胞介导的人低密度脂蛋白（LDL）修饰，这可通过硫代巴比妥酸反应性物质的产生、在一组新的巨噬细胞中刺激[125I]LDL降解以及LDL电泳迁移率来衡量，其呈剂量依赖性，在30 - 40微摩尔时完全抑制。当驻留巨噬细胞在甲吡酮、甲氧沙林和α - 萘黄酮存在下与LDL一起孵育时，这些物质的浓度已被证明可抑制细胞色素P450依赖性加氧酶，但LDL修饰没有变化。巨噬细胞与苯并[a]芘孵育24小时诱导苯并[a]芘羟化酶活性，同时LDL修饰增加1.5倍，酮康唑以及甲氧沙林和α - 萘黄酮可使其恢复到原有水平。此外，酮康唑有效减少了铁而非铜离子诱导的无细胞LDL氧化，并降低了巨噬细胞的自发和酵母聚糖刺激的光泽精增强化学发光。这些数据使我们认为酮康唑通过作为铁螯合剂和/或含铁酶促氧化剂形式的抑制剂来抑制LDL氧化。
