茶碱代谢在人类肝微粒体:抑制研究。
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Tjia摩根富林明,科尔伯特J, DJ
茶碱代谢在人类肝微粒体:抑制研究。
J Exp其他杂志》1996年3月,276 (3):912 - 7。
- PubMed ID
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8786569 (在PubMed]
- 文摘
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在本文中,我们描述的生成动力学1-methylxanthine (1-MX) 3-methylxanthine (3 mx)和1,3-dimethyluric酸(1,3-DMU)茶碱在人类肝微粒体孵化项目和使用的选择性抑制剂方法定义的角色个体细胞色素p450 (CYP)在每个通路。两相的模型拟合的数据最好每个代谢产物的形成。网站的高亲和性公里和Vmax值是:1-MX,公里= 0.29 + / - 0.21毫米,= 5.92 + / - 3.74 pmol.mg .min(1)(1)(意味着美国南达科他州+ / -;n = 4);3 mx,公里= 0.28 + / - 0.08毫米,Vmax = 3.32 + / - 2.19 pmol.mg (1) .min (1);1、3-DMU公里= 0.31 + / - 0.14毫米,= 43.3 + / - 9.3 pmol.mg (1) .min (1)。的相对贡献高和低亲和力酶1,3-DMU形成基于酶动力学参数的计算。描述网站的高亲和性,一系列CYP同工酶底物和抑制剂与100年孵化microM茶碱。CYP1A2抑制剂furafylline, ellipticine和alpha-naphthoflavone 1-MX和3 mx形成强有力的抑制剂有80%的抑制浓度低于5 microM N-demethylase活动。这些化合物也明显抑制1,3-DMU形成。 Enzyme kinetic and selective inhibition data indicated that about 80% of 1,3-DMU formation was catalyzed by the high-affinity isoform (CYP1A2) at a theophylline concentration of 100 microM. To investigate the role of other isoforms in 8-hydroxylation, experiments were performed involving incubation with a combination of inhibitors. It is evident that in addition to CYP1A2, CYP2E1 has a minor role om 8-hydroxylation. This based on the fact that 80% inhibition was seen on preincubation with furafylline and about 90% inhibition on preincubation with furafylline plus diethyldithiocarbamate. Low concentrations of ketoconazole (selective for CYP3A4) only produced marginal inhibition of 1,3-DMU and, therefore, CYP3A4 is only of minor significance in this reaction. Human B-lymphoblastoid cell lines expressing CYP1A2 catalyzed theophylline metabolism with formation of 1-MX, 3-MX and 1,3-MDU. CYP2E1 cells also catalyzed formation of 1,3-DMU. The CYP3A4 cell line did not catalyze theophylline metabolism.
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