Enhanced Susceptibility of HLA-mediated Ticlopidine-induced Idiosyncratic Hepatotoxicity by CYP2B6 Polymorphism in Japanese
Enhanced Susceptibility of HLA-mediated Ticlopidine-induced Idiosyncratic Hepatotoxicity by CYP2B6 Polymorphism in Japanese
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DOI：
10.2133/dmpk.25.298
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发表时间：
2010-01-01
影响因子：
2.1
通讯作者：
Kitada, Mitsukazu
中科院分区：
文献类型：
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作者：
Ariyoshi, Noritaka;Iga, Yukako;Kitada, Mitsukazu
肝毒性是日本人噻氯匹定（TP）最常见的不良反应。我们在114名日本患者中调查了CYP 2B 6单倍型与TP诱导的肝毒性发生率之间的关系。在对照组（n = 81）和病例组（n = 22）中，4种单倍型（*1A，*1H，* 1 J和 * 6 B）占推断单倍型的80%以上，但其患病率明显不同：对照组为 *1A > * 6 B> *1H> * 1 J，病例组为 * 1 J> *1H> *1A> * 6 B。报告基因分析表明，* 1H和 * 1 J单倍型可能与CYP 2B 6表达增加有关，可能是由于g. -2320TAC。CYP 2B 6和人类白细胞抗原（HLA）单倍型联合分析显示，CYP 2B 6 *1H或 * 1 J和HLA-A*3303的个体对TP诱导的肝毒性的易感性最高（比值比，38.82，95%CI，8.08-196.0，P < 0.001）。虽然这是一个初步的病例对照研究，有一定的局限性，这是第一个例子，HLA诱导的特异质ADR可能被修改的个体差异，在抗肿瘤活性。
Hepatotoxicity is the most frequent adverse drug reaction (ADR) in Japanese treated with ticlopidine (TP). We investigated the relationship between CYP2B6 haplotype and incidence of TP-induced hepatotoxicity in 114 Japanese patients. Although 4 haplotypes (*1A, *1H, *1J and *6B) accounted for more than 80% of the inferred haplotypes in both control (n = 81) and case (n = 22) subjects, the prevalence was apparently different: control, *1A > *6B> *1H> *1J and case, *1J> *1H> *1A> *6B. The reporter gene assay for the two SNPs, which comprise the *1H or *1J haplotype, suggested that the *1H and *1J haplotypes may be associated with the increased expression of CYP2B6, probably due to g. -2320TAC. Combination analysis of CYP2B6 and human leukocyte antigen (HLA) haplotypes revealed that individuals possessing CYP2B6*1H or *1J with HLA-A*3303 have the highest susceptibility to TP-induced hepatotoxicity (odds ratio, 38.82; 95%CI, 8.08-196.0, P < 0.001). Although this is a preliminary case-control study with some limitations, it is the first example that HLA-induced idiosyncratic ADR may be modified by individual variation in CYP activities.