Lupp A, Kerst S, Karge E, Quack G, Klinger W
Institute of Pharmacology and Toxicology, Friedrich Schiller University Jena, Germany.
Exp Toxicol Pathol. 1998 Sep;50(4-6):501-6. doi: 10.1016/S0940-2993(98)80041-9.
Possible antioxidative properties of three N-methyl-D-aspartate (NMDA)-receptor antagonists, the anesthetic ketamine and the antiparkinson drugs memantine and amantadine were investigated in vitro on the microsomal cytochrome P450 (P450) system of rat livers and on rat whole blood chemiluminescence in comparison to nicanartine, a substance with known antiatherosclerotic, hypolipemic and antioxidative capacity. For this purpose, the effects on NADPH- and iron-stimulated lipid peroxidation (LPO), hydrogen peroxide (H2O2) production, and NADPH- and iron-stimulated lucigenin (LC) and luminol (LM) amplified chemiluminescence (CL) were examined using rat liver microsomes. Additionally, the influence on LM amplified whole blood chemiluminescence after zymosan activation of polymorphonuclear leukocytes (WB-CL) was investigated. Furthermore, binding to P450 and effects on P450 mediated monooxygenase function, as measured by the model reactions ethoxyresorufin O-deethylation (EROD), ethoxycoumarin O-deethylation (ECOD), and ethylmorphine N-demethylation (END), were assessed. Nicanartine concentration dependently reduced LPO and H2O2 production already at a concentration of 1 microM, whereas LC and LM amplified CL and WB-CL were not affected. EROD and END were concentration dependently diminished starting at 1 microM, and ECOD already at 0.1 microM. Ketamine decreased LPO, H2O2 production and LM and LC amplified CL, starting at 100 microM. WB-CL was significantly diminished already at 10 microM. EROD and ECOD were inhibited at 10 and 100 microM and END at 100 microM. With memantine a concentration dependent inhibition of LPO and WB-CL was seen at 100 and 1000 microM and a reduction of LC and LM amplified CL only at 1000 microM. H2O2 production was not affected. EROD and ECOD were significantly diminished by a concentration of 100 microM. No effect was observed on END. Amantadine significantly reduced LPO and WB-CL, but only at 1000 microM. H2O2 production and LC and LM amplified CL were not affected. EROD was significantly diminished at 100 microM, whereas no influence was seen on ECOD and END. Nicanartine displayed type II or reverse type I, ketamine, memantine and amantadine type I substrate binding to P450. The highest binding affinity to P450 was seen with nicanartine, followed by ketamine, memantine and then amantadine. These results demonstrate, that all four substances seem to act as radical scavengers and/or as inhibitors of the oxidative function of P450. All four substances seem to interfere with the monooxygenase function of P450. This may result in a possible influence on the biotransformation of endogenous as well as of foreign compounds. The effects of nicanartine were much more pronounced than those of ketamine, memantine, and amantadine.
研究了三种N-甲基-D-天冬氨酸（NMDA）受体拮抗剂（麻醉剂氯胺酮以及抗帕金森病药物美金刚和金刚烷胺）与具有已知抗动脉粥样硬化、降血脂和抗氧化能力的尼卡芦丁相比，在大鼠肝脏微粒体细胞色素P450（P450）系统和大鼠全血化学发光方面的体外抗氧化特性。为此，使用大鼠肝脏微粒体检测了对NADPH和铁刺激的脂质过氧化（LPO）、过氧化氢（H2O2）生成以及NADPH和铁刺激的光泽精（LC）和鲁米诺（LM）放大化学发光（CL）的影响。此外，还研究了对酵母聚糖激活多形核白细胞后LM放大的全血化学发光（WB-CL）的影响。此外，通过乙氧异吩恶唑酮-O-脱乙基酶（EROD）、乙氧香豆素-O-脱乙基酶（ECOD）和N-脱甲基化反应（END）等模型反应评估了与P450的结合以及对P450介导的单加氧酶功能的影响。尼卡芦丁在1μM浓度时就浓度依赖性地降低LPO和H2O2生成，而LC和LM放大的CL以及WB-CL不受影响。从1μM开始，EROD和END呈浓度依赖性降低，ECOD在0.1μM时就开始降低。氯胺酮从100μM开始降低LPO、H2O2生成以及LM和LC放大的CL。WB-CL在10μM时就显著降低。EROD和ECOD在10和100μM时受到抑制，END在100μM时受到抑制。美金刚在100和1000μM时可见对LPO和WB-CL的浓度依赖性抑制，仅在1000μM时降低LC和LM放大的CL。H2O2生成不受影响。100μM浓度时EROD和ECOD显著降低。未观察到对END的影响。金刚烷胺仅在1000μM时显著降低LPO和WB-CL。H2O2生成以及LC和LM放大的CL不受影响。100μM时EROD显著降低，而未观察到对ECOD和END的影响。尼卡芦丁表现出II型或反I型，氯胺酮、美金刚和金刚烷胺表现出I型与P450的底物结合。尼卡芦丁对P450的结合亲和力最高，其次是氯胺酮、美金刚，然后是金刚烷胺。这些结果表明，所有四种物质似乎都作为自由基清除剂和/或P450氧化功能的抑制剂起作用。所有四种物质似乎都干扰P450的单加氧酶功能。这可能对内源性和外源性化合物的生物转化产生可能的影响。尼卡芦丁的作用比氯胺酮、美金刚和金刚烷胺的作用更为明显。
