THE DIHYDROPYRIMIDINE DEHYDROGENASE POLYMORPHISM

二氢嘧啶脱氢酶(DPD)是体内代谢的限速酶。 导致嘧啶分解代谢的代谢途径。分解代谢 尿嘧啶的合成也会导致B-丙氨酸的合成。因此，DPD是一种 中间代谢中的关键酶。此外，DPD是 负责化疗药物5-氟尿嘧啶的分解代谢。 在以下情况下表现出毒性的患者中发现DPD缺乏 注射5-氟尿嘧啶。这些受试者的平均淋巴细胞DPD 活动的数量是平均人口的一半。一个 完全缺乏DPD活性与各种出生有关 受影响个体的缺陷。确定DPD的发病机制 并开发了一种针对这种缺陷的诊断测试，即人类DPD 分离了DPD基因，并对突变的DPD基因进行了鉴定。荷兰人 有一个孩子缺乏DPD活动的家庭进行了反向分析 转录酶-聚合酶链式反应(RT-PCR)。这里面的DPD基因 一家人被发现编码了一个缺失外显子的有缺陷的RNA转录本 这是由于前mRNA剪接过程中的外显子跳跃所致。受影响的孩子 是缺陷的DPD基因的纯合子。完整的DPD基因是 克隆在两个重叠的巨型YAC中，目前正在进行测序。 这将允许对缺陷的DPD基因进行直接测序 个人。

Dihydropyrimidine dehydrogenase (DPD) is the rate limiting enzyme in the metabolic pathway leading to the catabolism of pyrimidines. Catabolism of uracil also results in the synthesis of B-alanine. Thus, DPD is a critical enzyme in intermediary metabolism. In addition, DPD is responsible for catabolism of the chemotherapeutic drug, 5-fluorouracil. A deficiency in DPD was detected in patients who exhibited toxicity when administered 5-fluorouracil. These subjects had mean lymphocyte DPD activities that were one-half those of the average population. A complete lack of DPD activity has been associated with a variety of birth defects in affected individuals. To determine the mechanism of the DPD deficiency and to develop a diagnostic test for the defect, the human DPD cDNA gene was isolated and mutant DPD genes were characterized. A Dutch family having a child lacking DPD activity was analyzed by reverse transcriptase-polymerase chain reaction (RT-PCR). The DPD gene in this family was found to encode a defective RNA transcript that lacked an exon due to exon skipping during the pre-mRNA splicing. The affected child was homozygous for the defective DPD gene. The complete DPD gene was cloned in two overlapping mega YACS and is currently being sequenced. This will allow the direct sequencing of DPD genes from deficient individuals.