Ezzeldin Hany, Johnson Martin R, Okamoto Yoshihiro, Diasio Robert
University of Alabama at Birmingham, Division of Clinical Pharmacology and Toxicology, Comprehensive Cancer Center, Birmingham, Alabama 35294-3300, USA.
Clin Cancer Res. 2003 Aug 1;9(8):3021-8.
Dihydropyrimidine dehydrogenase (DPD) enzyme deficiency is a pharmacogenetic syndrome with possible fatal outcome following 5-fluorouracil (5-FU) treatment. Several studies examining the molecular basis for DPD deficiency have identified over 30 sequence variations in the DPYD gene (which codes for the DPD enzyme). Our laboratory has recently developed and validated a denaturing high performance liquid chromatography method capable of identifying both known and unknown sequence variations in the DPYD gene. In the present study, we used this denaturing high performance liquid chromatography approach to examine the DPYD genotype of three patients who experienced lethal toxicity after administration of 5-FU. DPD enzyme activity could only be measured in one patient before death and demonstrated that lethal toxicity can occur in a partially DPD-deficient individual. Multiple heterozygous sequence variations (both known and unknown) were detected in all three patients including the novel variants 545T>A, M182K and 2329G>T, A777S. We conclude that (a) lethal toxicity can occur in partially DPD-deficient individuals after administration of 5-FU and is not exclusive to profoundly DPD-deficient individuals as suggested previously, (b) the complicated heterozygote genotype seen in these patients, combined with DPD deficiency being an autosomal codominant inherited syndrome, precludes the use of simple genotyping assays that identify only one or two mutations as a method for identifying DPD-deficient individuals; and (c) these multiple heterozygote genotypes (which are more difficult to accurately characterize) may be responsible for some of the conflicting reports which suggests a lack of correlation between phenotype and genotype.
二氢嘧啶脱氢酶（DPD）缺乏症是一种药物遗传学综合征，5-氟尿嘧啶（5-FU）治疗后可能产生致命后果。多项研究探讨了DPD缺乏症的分子基础，已在DPYD基因（编码DPD酶）中鉴定出30多种序列变异。我们实验室最近开发并验证了一种变性高效液相色谱法，能够识别DPYD基因中的已知和未知序列变异。在本研究中，我们使用这种变性高效液相色谱方法检测了3例接受5-FU治疗后出现致命毒性的患者的DPYD基因型。仅在1例患者死亡前检测到了DPD酶活性，表明部分DPD缺乏的个体也可能发生致命毒性。在所有3例患者中均检测到多个杂合序列变异（包括已知和未知的），其中包括新的变异545T>A、M182K、2329G>T和A777S。我们得出以下结论：（a）5-FU给药后，部分DPD缺乏的个体可能发生致命毒性，并非如之前所认为的仅发生于严重DPD缺乏的个体；（b）这些患者中所见的复杂杂合子基因型，加上DPD缺乏是一种常染色体共显性遗传综合征，使得仅识别一两个突变的简单基因分型检测方法无法用于识别DPD缺乏个体；（c）这些多个杂合子基因型（更难以准确表征）可能是一些相互矛盾的报告的原因，这些报告表明表型与基因型之间缺乏相关性。
