DPYD基因多态性及其功能活性与首次使用氟尿嘧啶药物毒性的相关性

Correlation between DPYD gene polymorphism and its functional activity and toxicity of first-time fluorouracil drug

目的:探究由DPYD(rs3918290,rs55886062和rs67376798)基因多态性引起DPYD酶功能发生变化,进而导致患者氟尿嘧啶化学药物治疗(以下简称化疗)化疗方案药物毒性反应的机制。方法:收集南通大学附属东台医院肿瘤科103例单独使用氟尿嘧啶化疗方案患者的全血样本,按照氟尿嘧啶化疗方案药物毒性反应情况分为无药物毒性组、1~2级药物毒性组和3~4级药物毒性组。使用RT-PCR和蛋白质印迹法测定两组患者DPYD的mRNA和蛋白质的表达水平,使用原位杂交技术检测DPYD(rs3918290,rs55886062和rs67376798)位点在3组患者基因型频率的分布情况。结果:与无药物毒性组和1~2级药物毒性组相比,3~4级药物毒性组的DPYD的mRNA和蛋白质表达水平明显升高,DPYD(rs3918290,rs55886062和rs67376798)位点各基因型频率在两组患者中的分布差异有统计学意义(P<0.05)。结论:DPYD mRNA的过表达与氟尿嘧啶药物毒性反应的发生密切相关。DPYD(rs3918290,rs55886062和rs67376798)基因多态性可能与氟尿嘧啶药物毒性显著相关。DPYD(rs3918290,rs55886062和rs67376798)基因突变导致DPYD基因功能上调进而促进氟尿嘧啶药物毒性的发生。

Objective:To investigate the mechanism of DPYD(rs3918290,rs55886062 and rs67376798)gene polymorphisms lead to changes in the function of DPYD enzymes,leading to the toxic reaction of patients with fluorouracil chemotherapy.Methods:A total of 100 patients with fluorouracil chemotherapy were enrolled in the oncology department.According to the toxicity of fluorouracil chemotherapy,the drug toxicity group was divided into non-drug toxicity group,mild drug toxicity group and moderate to severe drug toxicity group.The mRNA and protein expression levels of DPYD in the two groups were determined by RT-PCR and Western blot.The distribution of DPYD(rs3918290,rs55886062 and rs67376798)sites in the genotype frequencies of the three groups was detected by in situ hybridization.Three sets of clinical sample data were analyzed by analysis of variance and chi-square test.Results:Compared with the non-drug-toxic group and the mild drug-toxic group,the mRNA and protein expression levels of DPYD in the drug-toxic group of grade 3 to 4 were significantly increased.The frequencies of the genotypes of DPYD(rs3918290,rs55886062 and rs67376798)were two.There was a significant difference in the distribution among the patients(P<0.05).Conclusion:Overexpression of DPYD mRNA is closely related to the occurrence of fluorouracil drug toxicity.The polymorphisms of DPYD(rs3918290,rs55886062 and rs67376798)may be significantly associated with fluorouracil drug toxicity.The mutation of DPYD(rs3918290,rs55886062 and rs67376798)leads to the upregulation of DPYD gene and promotes the toxicity of fluorouracil.