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首页> 外文期刊>Pharmacogenetics and genomics >Genetic regulation of dihydropyrimidinase and its possible implication in altered uracil catabolism.
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Genetic regulation of dihydropyrimidinase and its possible implication in altered uracil catabolism.

机译：二氢嘧啶酶的遗传调控及其在改变的尿嘧啶分解代谢中的可能意义。

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OBJECTIVE: Dihydropyrimidine dehydrogenase (DPD) deficiency accounts for approximately 43% of grade 3-4 toxicity to 5-fluorouracil. There, however, remain a number of patients presenting with 5-fluorouracil-associated toxicity despite normal DPD enzyme activity, suggesting possible deficiencies in dihydropyrimidinase (DHP), encoded by the DPYS gene, and/or beta-ureidopropionase (BUP-1), encoded by the UPB1 gene. This study investigates the role of DPYS sequence variations in individuals with unexplained molecular basis of altered uracil catabolism. METHODS: This study included 219 asymptomatic healthy volunteers with known DPD enzyme activity and [2-13C]-uracil breath test (UraBT) profiles. All samples were genotyped for sequence variations in the DPYS gene using denaturing high-performance liquid chromatography (DHPLC) and Surveyor enzyme digestion with confirmation by direct sequencing. Site-directed mutagenesis and expression analysis were performed to determine the effect of the identified nonconservative mutations on DHP enzyme activity. RESULTS: Seven previously reported and 11 novel sequence variations were identified, including three nonconservative mutations; two of which (L7V and 1635delC) demonstrated decreased DHP activity when expressed in the RKO cell line (P=0.25). The P values were not significant due to the small sample size (n=3); however, a modified [2-13C]-uracil breath test, the 13C-dihydrouracil breath test, was administered to four volunteers to confirm that the 1635delC mutation does in fact reduce in-vivo DHP activity. CONCLUSION: Data presented in this study demonstrate that alterations of uracil catabolism are not limited to DPD deficiency, and that inactivating mutations in DHP might impair uracil catabolism in cases of normal DPD activity.
机译：目的：二氢嘧啶脱氢酶（DPD）缺乏约占对5-氟尿嘧啶3-4级毒性的43％。然而，尽管DPD酶活性正常，仍有许多患者出现5-氟尿嘧啶相关的毒性反应，提示DPYS基因和/或β-脲基丙酸酶（BUP-1）编码的二氢嘧啶酶（DHP）可能存在缺陷，由UPB1基因编码。这项研究调查了具有无法解释的尿嘧啶分解代谢的分子基础的个体中DPYS序列变异的作用。方法：这项研究包括219名无症状的健康志愿者，他们具有已知的DPD酶活性和[2-13C]-尿嘧啶呼气试验（UraBT）特征。使用变性高效液相色谱（DHPLC）和Surveyor酶消化，通过直接测序确认，对所有样品进行DPYS基因序列变异的基因分型。进行定点诱变和表达分析以确定所鉴定的非保守突变对DHP酶活性的影响。结果：确定了七个先前报道的和11个新的序列变异，包括三个非保守突变;当在RKO细胞系中表达时，其中两个（L7V和1635delC）证明DHP活性降低（P = 0.25）。由于样本量小（n = 3），P值不显着。但是，对四名志愿者进行了改良的[2-13C]-尿嘧啶呼气试验，即13C-二氢尿嘧啶呼气试验，以确认1635delC突变确实确实降低了体内DHP活性。结论：本研究中提供的数据表明尿嘧啶分解代谢的改变不仅限于DPD缺乏，在正常DPD活性的情况下，DHP中的失活突变可能会损害尿嘧啶分解代谢。

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