N-hydroxylation of dapsone by multiple enzymes of cytochrome P450: Implications for inhibition of haemotoxicity
N-hydroxylation of dapsone by multiple enzymes of cytochrome P450: Implications for inhibition of haemotoxicity
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DOI：
10.1111/j.1365-2125.1995.tb05797.x
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发表时间：
1995-12-01
影响因子：
3.4
通讯作者：
Park, BK
中科院分区：
文献类型：
--
作者：
Gill, HJ;Tingle, MD;Park, BK
与给药氨苯砜相关的不良反应被认为是由代谢其羟胺引起的。先前的报道表明CYP3A4负责这种生物转化[1].2在本文中提出的数据说明了一个以上的细胞色素P450酶参与氨苯砜羟胺形成使用人肝微粒体。edie - hofstee图显示了几个肝脏的双相动力学。6人肝脏羟胺形成与CYP3A浓度之间无相关性（r = -0.47; P = 0.34）低分子量抑制剂的研究表明CYP2C9和CYP3A在氨苯砜n -羟基化中的重要性氨苯砜n -羟基化对选择性CYP抑制剂的不同敏感性表明，不同肝脏的CYP酶的作用不同。5亩M酮康唑的选择性抑制率为6.8 ~ 44.4%，100亩M磺胺苯唑的选择性抑制率为24.0 ~ 68.4%。酮康唑或磺胺苯唑的抑制程度取决于肝脏中CYP3A的含量这些细胞色素P450酶的表达水平可能是个体对氨苯砜毒性作用易感性的重要决定因素，并可能影响酶抑制剂在体内阻断氨苯砜毒性的能力。由于不能产生完全的抑制作用，选择性CYP抑制剂在减少体内氨苯砜羟胺形成方面不太可能比西咪替丁提供任何临床优势。
1 The adverse reactions associated with the administration of dapsone are believed to be caused by metabolism to its hydroxylamine. Previous reports suggest that CYP3A4 is responsible for this biotransformation [1].2 Data presented in this paper illustrate the involvement of more than one cytochrome P450 enzyme in dapsone hydroxylamine formation using human liver microsomes. Eadie-Hofstee plots demonstrated bi-phasic kinetics in several livers. No correlation could be established between hydroxylamine formation and CYP3A concentrations in six human livers (r = -0.47; P = 0.34).3 Studies with low molecular weight inhibitors illustrate the importance of CYP2C9 and CYP3A in dapsone N-hydroxylation.4 Differential sensitivity of dapsone N-hydroxylation to selective CYP inhibitors indicated that the contribution of individual CYP enzymes varies between livers. Selective inhibition ranged from 6.8 to 44.4% by 5 mu M ketoconazole, and from 24.0 to 68.4% by 100 mu M sulphaphenazole. The extent of inhibition, by either ketoconazole or sulphaphenazole was dependent on the CYP3A content of the liver.5 The levels of expression of these cytochrome P450 enzymes may be an important determinant of individual susceptibility to the toxic effects of dapsone, and may influence the ability of an enzyme inhibitor to block dapsone toxicity in vivo. Because of the inability to produce complete inhibition, selective CYP inhibitors are unlikely to offer any clinical advantage over cimetidine in decreasing dapsone hydroxylamine formation in vivo.