系统,抑制细胞色素P450 (CYP) 2 chalepensin a6的重组系统,在人肝微粒体和老鼠体内。

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Ueng YF,陈CC,钟欧美,刘泰,Chang YP,瞧WS, Murayama N,山崎H, Soucek P,洲GY,连续波,RM陈,李DT

系统,抑制细胞色素P450 (CYP) 2 chalepensin a6的重组系统,在人肝微粒体和老鼠体内。

Br J杂志。2011年7月,163 (6):1250 - 62。doi: 10.1111 / j.1476-5381.2011.01341.x。

PubMed ID

21418183 (在PubMed

]

文摘

背景和目的:Chalepensin街中含有的药物活性furanocoumarin化合物,草药。这里我们有调查的抑制作用对细胞色素P450 (CYP) 2 chalepensin a6在体外和体内。实验方法:系统,研究了抑制肝微粒体体外用人类和细菌细胞膜表达人类体内CYP2A6基因表现的遗传变异。影响体内在C57BL / 6 j小鼠进行了研究。体内CYP2A6基因表现活动是化验香豆素7-hydroxylation (CH)使用高效液相色谱法和荧光测量。chalepensin代谢评估与液相色谱/质谱(LC / MS)。主要结果:CYP2A6.1,没有pre-incubation NADPH,被chalepensin竞争性抑制。用NADPH pre-incubation后,抑制chalepensin增加(IC(50)值下降了98%)。这个时间失活(k(非活性的)0.044分钟(1);K (I) 2.64 microM)引起的损失幽灵似地探测P450含量减少体内CYP2A6基因表现的已知的抑制剂,毛果芸香碱或强内心百乐明,谷胱甘肽共轭。 LC/MS analysis of chalepensin metabolites suggested an unstable epoxide intermediate was formed, identified as the corresponding dihydrodiol, which was then conjugated with glutathione. Compared with the wild-type CYP2A6.1, the isoforms CYP2A6.7 and CYP2A6.10 were less inhibited. In mouse liver microsomes, pre-incubation enhanced inhibition of CH activity. Oral administration of chalepensin to mice reduced hepatic CH activity ex vivo. CONCLUSIONS AND IMPLICATIONS: Chalepensin was a substrate and a mechanism-based inhibitor of human CYP2A6. Formation of an epoxide could be a key step in this inactivation. 'Poor metabolizers' carrying CYP2A6*7 or *10 may be less susceptible to inhibition by chalepensin. Given in vivo, chalepensin decreased CYP2A activity in mice.

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药物酶

药物	酶	类	生物	药理作用	行动
毛果芸香碱	细胞色素P450 2 a6	蛋白质	人类	未知的	抑制剂	细节