人类和老鼠P450酶的识别负责sulfoxidation S-methyl N, N-diethylthiolcarbamate (DETC-ME)。终端一步bioactivation戒酒硫。

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马丹,帕金森,Faiman MD

人类和老鼠P450酶的识别负责sulfoxidation S-methyl N, N-diethylthiolcarbamate (DETC-ME)。终端一步bioactivation戒酒硫。

药物金属底座Dispos。1995年10月;23 (10):1153 - 62。

PubMed ID

8654205 (在PubMed

]

文摘

本研究调查了老鼠和人类细胞色素P450酶的作用的sulfoxidation S-methyl N, N-diethylthiolcarbamate (DETC-Me) S-methyl N, N-diathylthiolcarbamate亚砜(DETC-Me亚砜),戒酒硫的假定的活性代谢物。DETC-Me sulfoxidation雄性和雌性大鼠的微粒体处理各种细胞色素p450酶诱导建议多个酶可以催化这个反应,其中包括,CYP1A1/2 CYP2B1/2, CYP3A1/2。检查所有cDNA-expressed人类细胞色素P450酶催化的sulfoxidation DETC-Me。流动率(最低为1)的DETC-Me cDNA-expressed sulfoxidation的细胞色素P450酶排名如下:CYP3A4体内CYP2A6基因表现> = CYP2C9 > CYP1A2 > CYP2B6 = CYP2D6 CYP2E1 > CYP1A1 >。有趣的是,CYP3A4排名第一或最后,取决于是否额外NADPH-cytochrome P450还原酶是lymphoblastoid coexpressed细胞。这个复杂的估计CYP3A4的贡献DETC-Me sulfoxidation由人类肝脏微粒体。银行的样本变异DETC-Me sulfoxidation人类肝脏微粒体(N = 13)与香豆素7-hydroxylation高度相关(r = 0.88)和睾酮6 beta-hydroxylation (r = 0.90),表明体内CYP2A6基因表现和CYP3A4/5有助于sulfoxidation DETC-Me由人类肝脏微粒体。虽然chlorzoxazone 6-hydroxylation (CYP2E1的标志)相关差DETC-Me sulfoxidation,相关改进的r = 0.07 r = 0.44时DETC-Me sulfoxidation研究在体内CYP2A6基因表现抑制剂的存在,香豆素。同样的,当DETC-Me sulfoxidation研究在二乙基二硫代氨基甲酸(DDTC)的抑制DETC-Me sulfoxidase活动相关(r = 0.50)更好chlorzoxazone 6-hydroxylase,相比之下,DETC-Me sulfoxidase活动缺乏DDTC (r = 0.09)。多克隆抗体CYP2E1造成适度抑制(30%)的DETC-Me sulfoxidation由人类肝脏微粒体。 Anti-CYP3A1 antibodies completely inhibited DETC-Me sulfoxidation by cDNA-expressed CYP3A4. Under similar conditions, DETC-Me sulfoxidation by human liver microsomes was only partially inhibited by anti-CYP3A1 antibodies. Although studies with the rat and cDNA-expressed cytochrome P450 enzymes suggested that CYP1A2 contributed to DETC-Me sulfoxidation, this reaction was not inhibited by either furafylline ( a mechanism-based inhibitor of CYP1A2) or antibodies against CYP1A1/2. A significant role for CYP2C9 was excluded by the inability of sulfaphenazole to inhibit the sulfoxidation of DETC-Me by human liver microsomes. Collectively, these data suggest that multiple cytochrome P450 enzymes can catalyze the sulfoxidation of DETC-Me. In human liver microsomes the CYP2A6, CYP2E1, and CYP3A4/5 all contribute significantly to the sulfoxidation of DETC-Me. It is interesting to note that DDTC, the reduced metabolite of disulfiram, is known to inhibit these same enzymes. The ability of DDTC to block the formation of DETC-Me sulfoxide may explain why the dose of disulfiram required to produce a disulfiram-ethanol reaction in alcoholics is so variable and often inadequate.

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药物酶

药物	酶	类	生物	药理作用	行动
戒酒硫	细胞色素P450 3 a4	蛋白质	人类	未知的	底物	细节
戒酒硫	细胞色素P450 3 a5	蛋白质	人类	未知的	底物	细节