描述的右美沙芬去人类肝脏微粒体。贡献的细胞色素P450 3亚科(CYP3A)。

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Gorski JC,琼斯博士,SD Wrighton SA大厅

描述的右美沙芬去人类肝脏微粒体。贡献的细胞色素P450 3亚科(CYP3A)。

生物化学杂志。1994年7月5日,48 (1):173 - 82。0006 - 2952 . doi: 10.1016 / (94) 90237 - 2。

PubMed ID

8043020 (在PubMed

]

文摘

为了识别人类细胞色素P450参与去右美沙芬,3-methoxymorphinan形成的动力学研究了微粒体酶系统。在初始速率条件下,3-methoxymorphinan形成了单一的酶Michaelis-Menten动力学使用获得从三个人类肝脏微粒体(公里:0.52 - -0.71毫米;Vmax: 375 - 812 pmol /毫克蛋白/分钟)。B-lymphoblastoid细胞表达CYP3A4孵化与0.4毫米右美沙芬催化形成的速度3-methoxymorphinan 22 pmol产品/毫克蛋白/分钟。咪达唑仑、衬底对CYP3A4和CYP3A5被竞争性抑制右美沙芬去的两个人类肝脏微粒体样品Ki值46 + / - 10和63 + / - 8 microM。右美沙芬浓度的0.4毫米,孕二烯酮(100 microM)抑制3-methoxymorphinan形成了大约50%。Immunoinhibition右美沙芬的去使用兔子anti-CYP3A4 3-methoxymorphinan形成抗体导致减少了60%的右美沙芬浓度使用furafylline 0.4毫米。额外的抑制研究,香豆素,sulfaphenazole,美芬妥因、奎尼丁、和diethyldithiocarbamic酸,CYP1A2的选择性抑制剂,体内CYP2A6基因表现,CYP2C8/9, CYP2Cmp, CYP2D6, CYP2E1,分别展示了没有实质性的去甲基化抑制右美沙芬。相关分析是使用的速度执行3-methoxymorphinan形成的浓度为1毫米右美沙芬和immunoquantified CYP1A2的水平,体内CYP2A6基因表现,CYP2C8, CYP2C9, CYP2C19、CYP2D6、CYP2E1, CYP3A4和CYP3A5及其相关催化活动特征。之间的显著相关性观察右美沙芬N-demethylase活动和咪达唑仑1 ' -和4-hydroxylase活动(r2 = 0.77和0.69分别N = 19日,P < 0.01);排除这些样本包含CYP3A4和CYP3A5相关性显著增加(r2 = 0.87和0.91分别N = 12, P < 0.01)。 In the absence of CYP3A5, a significant correlation was observed between 3-methoxymorphinan formation and the sample's erythromycin N-demethylase activity (r2 = 0.94, N = 12, P < 0.01), testosterone 6 beta-hydroxylase activity (r2 = 0.96, N = 7, P < 0.01) and relative immunoquantified levels of CYP3A4 (r2 = 0.96, N = 12, P < 0.01). Inclusion of those samples expressing CYP3A5 in addition to CYP3A4 reduced the magnitude of the observed correlation. No significant correlation between 3-methoxymorphinan formation and the sample's relative immunoquantified levels of or form-selective activity associated with CYP1A2, CYP2A6, CYP2C8, CYP2C9, CYP2C19 (or CYP2Cmp), CYP2D6, and CYP2E1 was observed. In conclusion, dextromethorphan N-demethylation appears to be catalyzed primarily by CYP3A4 and to a lesser extent by CYP3A5 in vitro in humans.(ABSTRACT TRUNCATED AT 400 WORDS)

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药物酶

药物	酶	类	生物	药理作用	行动
右美沙芬	细胞色素P450 3 a7	蛋白质	人类	未知的	底物	细节