CYP4F在人肝微粒体酶是主要的酶催化的O-demethylation抗寄生虫药物前体DB289 [2, 5-bis (4-amidinophenyl) furan-bis-O-methylamidoxime]。

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王MZ,瀑布司法院,Usuki E,张黄,大厅M,桥梁,罗文G,帕金森OT,斯蒂芬斯CE、艾伦·莱托泽尔丁,柏金DW, Tidwell RR,帕金森,潘恩MF,大厅里我

CYP4F在人肝微粒体酶是主要的酶催化的O-demethylation抗寄生虫药物前体DB289 [2, 5-bis (4-amidinophenyl) furan-bis-O-methylamidoxime]。

药物金属底座Dispos。2006年12月,34 (12):1985 - 94。doi: 10.1124 / dmd.106.010587。Epub 2006年9月22日。

PubMed ID

16997912 (在PubMed

]

文摘

DB289 [2, 5-bis (4-amidinophenyl) furan-bis-O-methylamidoxime]是强有力的抗biotransformed diamidine DB75 [2, 5-bis (4-amidinophenyl)呋喃]顺序氧化O-demethylation和还原N-dehydroxylation反应。以前的工作表明,N-dehydroxylation反应由细胞色素b5 / NADH-cytochrome b5还原酶催化。酶负责催化DB289 O-demethylation通路尚未确定。我们报告一个体外代谢研究”来形容人类肝微粒体酶(高)催化的初始O-demethylation DB289 (M1)形成。有效抑制由1-aminobenzotriazole证实M1的形成是由P450酶催化的。M1形成由高级别NADPH-dependent, 0.5公里,Vmax microM和3.8 nmol /分钟/毫克蛋白,分别。初步筛选表明,重组CYP1A1、CYP1A2和CYP1B1 M1形成的高效催化剂。然而,这些三个酶负责M1形成问题。进一步筛选表明,重组CYP2J2、CYP4F2 CYP4F3B也可以催化M1的形成。对CYP4F2抗体,抑制CYP4F2和CYP4F3B,抑制91%的M1的形成问题。 Two inhibitors of P450-mediated arachidonic acid metabolism, HET0016 (N-hydroxy-N'-(4-n-butyl-2-methylphenyl)formamidine) and 17-octadecynoic acid, effectively inhibited M1 formation by HLMs. Inhibition studies with ebastine and antibodies against CYP2J2 suggested that CYP2J2 was not involved in M1 formation by HLMs. Additionally, ketoconazole preferentially inhibited CYP4F2, but not CYP4F3B, and partially inhibited M1 formation by HLMs. We conclude that CYP4F enzymes (e.g., CYP4F2, CYP4F3B) are the major enzymes responsible for M1 formation by HLMs. These findings indicate that, in human liver, members of the CYP4F subfamily biotransform not only endogenous compounds but also xenobiotics.

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药物酶

药物	酶	类	生物	药理作用	行动
酮康唑	Leukotriene-B (4) omega-hydroxylase 1	蛋白质	人类	未知的	抑制剂	细节