CYP3A4和CYP3A5基因多态性与骨髓移植患者服用环孢素A所致肝损伤的相关性

Correlation between CYP3A4 and CYP3A5 polymorphisms and the susceptibility of hepatic injury induced by cyclosporine A in bone marrow transplant recipients

目的:检测骨髓移植患者CYP3A4*18B和CYP3A5*3基因型分布特征,探讨CYP3A4和CYP3A5基因多态性与骨髓移植患者服用环孢素A(cyclosporine A,CsA)所致肝损伤的相关性。方法:骨髓移植患者112例,肝功正常73例,肝功异常39例;测定CsA给药1周后的稳态血药浓度,应用聚合酶链反应(PCR)后直接测序的方法检测CYP3A4*18B和CYP3A5*3基因型分布及等位基因频率。结果:与肝功正常患者比较,肝功异常患者CYP3A4*18B和CYP3A5*3基因型及等位基因分布频率均无显著性差异(P>0.05);与CYP3A5*1/*1和CYP3A5*1/*3基因型比较,携带CYP3A5*3/*3基因型患者使用CsA1周后的标准化血药浓度(concentration-dose ratios,CDR)显著升高(P<0.05)。结论:携带CYP3A5*3/*3的患者CsA的CDR升高,CYP3A5*3基因多态性可能与骨髓移植患者服用CsA所致肝损伤相关。

OBJECTIVE To study the frequency distribution patterns of CYP3A4 ＊ 18B and CYP3A5 ＊ 3 polymorphisms in bone marrow transplant recipients, to explore the correlation between CYP3A4 and CYP3A5 polymorphisms and the suscepti- bility of hepatic injury induced by CsA in bone marrow transplant recipients. METHODS 112 cases of bone marrow transplant recipients were totally collected, 73 cases with normal hepatic function and 39 cases with abnormal hepatic function. The steady state concentration of CsA （C0） was measured after 1 week of administration using FPIA method. Polymerase chain reaction- direct sequencing methods were used to detect the genotype of CYP3A4 ＊ 18B and CYP3A5＊ 3. RESUILTS There were no sig- nificant differences in the distribution of genotype of CYP3A4 ＊ 18B and CYP3A5 ＊ 3 between the groups of normal hepatic function and abnormal hepatic function （P）0.05）; Compared with the genotypes CYP3A5 ＊ 1/＊ 1 and CYP3A5 ＊ 1/＊ 3 CDR of CsA was increased significantly in recipients with CYP3A5 ＊ 3/＊ 3 （P〈0. 05）. CONCLUSION CYP3A5＊ 3 polymorphisms may be correlated with much higher CDR of CsA. Therefore, we speculate that CYP3A5 ＊ 3 may be a meaningful predictor of hepatic injury induced by CsA in bone marrow transplant recipients.