The effect of genetic polymorphisms in CYP2C9 on sulphamethoxazole N-hydroxylation
The effect of genetic polymorphisms in CYP2C9 on sulphamethoxazole N-hydroxylation
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DOI：
10.1097/00008571-199902000-00007
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发表时间：
1999-02-01
期刊：
影响因子：
--
通讯作者：
Park, BK
中科院分区：
文献类型：
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作者：
Gill, HJ;Tjia, JF;Park, BK
磺胺甲恶唑经CYP 2C 9介导的生物活化为羟胺。本研究采用聚合酶链反应扩增和限制性片段长度多态性分析方法，研究了CYP 2C 9 Arg（144）→ Cys（CYP 2C 9 *2）和CYP 2C 9 Ile（359）→ Leu（CYP 2C 9 *3）多态性对磺胺甲恶唑N-羟基化的影响。通过高压液相色谱法测定了由细胞系和基因分型的人肝脏制备的微粒体中磺胺甲恶唑羟胺和甲羟基甲苯磺丁脲的形成。由表达等位基因变体CYP 2C 9-Cys（144）和CYP 2C 9-Leu（359）的细胞系制备的微粒体显示磺胺甲恶唑的固有清除率（Cl-int）分别降低3倍和20倍，与野生型相比，CYP 2C 9-Arg（144）。对于两种突变，甲苯磺丁脲也观察到Cl-int显著降低（P < 0.05）。在26例基因分型的人肝脏中，61.5%为野生型纯合子，26.9%为CYP 2C 9 *2杂合子，15.4%为CYP 2C 9 *3杂合子。未检测到纯合子突变肝脏。磺胺甲恶唑的N-羟基化反应与甲苯磺丁脲的甲基羟基化反应具有良好的相关性（r = 0.825）。然而，野生型肝脏（n = 6）与CYP 2C 9 *2杂合子肝脏（n = 5）或CYP 2C 9 *3突变杂合子肝脏（n = 3）之间磺胺甲恶唑N-羟基化或甲苯磺丁脲甲基羟基化的动力学参数无差异，CYP 2C 9 *2和CYP 2C 9 *3多态性可能对磺胺甲恶唑的生物活性有一定影响，特别是在纯合突变体个体中，这可能是对抗磺胺甲恶唑超敏反应的保护性因素。然而，考虑到纯合突变体的罕见性，其它代谢和免疫风险因素可能将主导个体易感性，Pharmacogenetics 9：43-53（C）1999 Lippincott威廉姆斯和威尔金斯。
Sulphamethoxazole undergoes CYP2C9-mediated bioactivation to a hydroxylamine. In this study, we investigated the effect of the CYP2C9Arg(144) to Cys (CYP2C9*2) and CYP2C9Ile(359) to Leu (CYP2C9*3) polymorphisms on sulphamethoxazole N-hydroxylation, Human livers were genotyped using polymerase chain reaction amplification and restriction fragment length polymorphism analysis. Formation of sulphamethoxazole hydroxylamine and methylhydroxy tolbutamide in microsomes prepared from cell lines and the genotyped human livers was determined by high-pressure liquid chromatography, Microsomes prepared from the cell line expressing the allelic variants CYP2C9-Cys(144) and CYP2C9-Leu(359) displayed a threefold and 20-fold decrease in intrinsic clearance (Cl-int) for sulphamethoxazole, respectively, when compared with the wild-type, CYP2C9-Arg(144). A significant decrease (P < 0.05) in Cl-int was also observed with tolbutamide for both mutations, Of the 26 human livers genotyped, 61.5% were homozygous wild-type, 26.9% were heterozygotes for CYP2C9*2 and 15.4% were heterozygotes for CYP2C9*3. No homozygous mutant livers were detected. There was a good correlation between sulphamethoxazole N-hydroxylation and tolbutamide methyl hydroxylation (r = 0.825). However there was no difference in the kinetic parameters for either sulphamethoxazole N-hydroxylation or tolbutamide methyl hydroxylation between the wild type livers (n = 6) and either the livers heterozygous for the CYP2C9*2 (n = 5) or the livers heterozygous for the CYP2C9*3 mutation (n = 3), The CYP2C9*2 and CYP2C9*3 polymorphisms may have some influence on the bioactivation of sulphamethoxazole, particularly in individuals who are homozygous mutants, and this could act as a protective factor against sulphamethoxazole hypersensitivity. However, given the rarity of homozygous mutants, it is likely that other metabolic and immunological risk factors will dominate individual susceptibility, Pharmacogenetics 9:43-53 (C) 1999 Lippincott Williams & Wilkins.