Genetic susceptibility to diclofenac-induced hepatotoxicity: Contribution of UGT2B7, CYP2C8, and ABCC2 genotypes
Genetic susceptibility to diclofenac-induced hepatotoxicity: Contribution of UGT2B7, CYP2C8, and ABCC2 genotypes
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DOI：
10.1053/j.gastro.2006.11.023
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发表时间：
2007-01-01
期刊：
影响因子：
29.4
通讯作者：
Day, Christopher P.
中科院分区：
文献类型：
--
作者：
Daly, Ann K.;Aithal, Guruprasad P.;Day, Christopher P.
背景和目标：双氯芬酸是一种广泛使用的非甾体抗炎药，在最近的几个系列研究中，双氯芬酸是引起特异质肝毒性的最常见药物之一，黄疸受试者的死亡率高达20%。我们假设肝毒性易感性与编码酶UGT 2B 7和CYP 2C 8（决定反应性双氯芬酸代谢物的形成）和编码转运蛋白MRP 2（促进反应性代谢物的胆汁排泄）的ABCC 2的基因多态性相关。研究方法：对24例（19例女性）年龄24-70岁（平均50.8岁）的双氯芬酸肝毒性患者、48例（35例女性）年龄22-77岁（平均52岁）的服用双氯芬酸0.3-20年（平均4年）未发生肝毒性的受试者（医院对照）和112例健康对照者进行了研究。对编码UGT 2117、CYP 2C 8和ABCC 2的基因中的几种多态性进行基因分型，并分配单倍型。结果如下：UGT 2B 7 *2等位基因在双氯芬酸肝毒性患者中比医院对照组（比值比[OR]，8.5，P = 0.03）和健康对照组（OR，7.7，P = 0.03）更常见。ABCC 2 C-24 T变异在肝毒性患者中比医院（OR，5.0，P =.005）和健康对照（OR 6.3，P =.0002）更常见。与医院对照组相比，患者的CYP 2C 8单倍型分布不同（P =.04）。结论：UGT 2B 7、CYP 2C 8和ABCC 2的等位基因变体可能易导致反应性双氯芬酸代谢产物的形成和蓄积，与双氯芬酸肝毒性相关。活性代谢物水平的增加可能导致蛋白质-地多芬酸加合物水平升高，随后导致肝毒性。
Background & Aims: Diclofenac is a widely used nonsteroidal anti-inflammatory drug and is among the most common drugs causing idiosyncratic hepatotoxicity in several recent series with up to 20% mortality in jaundiced subjects. We hypothesized that susceptibility to hepatotoxicity would be associated with genetic polymorphisms in the genes encoding the enzymes UGT2B7 and CYP2C8, which determine the formation of reactive diclofenac metabolites and in ABCC2 encoding the transporter MRP2 contributing to the biliary excretion of the reactive metabolite. Methods: Twenty-four patients (19 female) aged 24-70 (mean, 50.8) years who had suffered diclofenac hepatotoxicity, 48 subjects (35 female) aged 22-77 (mean, 52) years who were taking diclofenac for 0.3-20 (mean, 4) years without developing hepatotoxicity (hospital controls), and 112 healthy controls were investigated. Genotyping for several polymorphisms in the genes encoding UGT2117, CYP2C8, and ABCC2 was performed and haplotypes assigned. Results: The UGT2B7*2 allele was more common in diclofenac hepatotoxicity patients compared with hospital controls (odds ratio [OR], 8.5, P =.03) and healthy controls (OR, 7.7, P =.03). The ABCC2 C-24T variant was more common in hepatotoxicity patients compared with hospital (OR, 5.0, P =.005) and healthy controls (OR 6.3, P =.0002). Haplotype distributions for CYP2C8 were different in patients compared with hospital controls (P =.04). Conclusions: Allelic variants of UGT2B7 CYP2C8, and ABCC2, which may predispose to the formation and accumulation of reactive diclofenac metabolites are associated with diclofenac hepatotoxicity. Increased level of reactive metabolites may lead to higher levels of protein-didofenac adducts and subsequently hepatotoxicity.