Racial variability in haplotype frequencies of UGT1A1 and glucuronidation activity of a novel single nucleotide polymorphism 686C>T (P229L) found in an African-American
Racial variability in haplotype frequencies of UGT1A1 and glucuronidation activity of a novel single nucleotide polymorphism 686C>T (P229L) found in an African-American
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DOI：
10.1124/dmd.104.001800
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发表时间：
2005-03-01
影响因子：
3.9
通讯作者：
Hasegawa, R
中科院分区：
文献类型：
--
作者：
Kaniwa, N;Kurose, K;Hasegawa, R
对非裔美国人、高加索人和日本人的UDP-葡萄糖醛酸基转移酶1A1(UGT1A1)基因多态性的种族差异进行了研究。对苯巴比妥反应增强子模块中的-3279T和gt；G，TATA框中的TA重复序列，外显子1中的211G和gt；A(G71R)和686C>；A(P229Q)以及外显子5的3个单核苷酸多态(SNPs)(1813C>；T、1941C>；G和2042C>；G)进行了基因分型。含有前四种变异的8种单倍型(外显子1及其5‘侧翼区)被分配给每个个体。非裔美国人的优势单倍型为*28b(-3279G；TA(7)；211G；686C)(0.446)，而日本人为*1a(-3279T；TA(6)；211G；686C)(0.610)。*1a和*28b两种单倍型在高加索人中的频率相当。*6a(-3279T；TA(6)；211a；686C)是日本人特有的单倍型，而36b和*37B(-3279T；TA(5)和TA(8)；211G；686C)单倍型主要见于非裔美国人。虽然第2块(外显子2-5)中的三个SNP在日本人中完全连锁，但在非裔美国人或高加索人中并不完全连锁。三个人群中单倍型分布模式的这些差异表明，UGT1A1解毒药物的毒性谱可能存在种族差异。在一名非裔美国人中发现了一种新的SNP，686C>；T(P229L)。在COS-1细胞中表达的P229L UGT1A1对7-乙基-10-羟基喜树碱(SN-38)的固有清除能力约为野生型的3%。Western blotting和实时逆转录聚合酶链式反应的结果表明，该变异体的低葡萄糖醛酸化活性部分是由于其稳定性低所致。在7-乙基-10-[4-(1-哌啶基)-1-哌啶基]羧氧基喜树碱(CPT-11)治疗或高胆红素血症患者中，686C>；T变异可能导致高毒性。
Ethnic differences in genetic polymorphisms in UDP-glucuronosyl-transferase 1A1 (UGT1A1) were investigated among African-Americans, Caucasians, and Japanese using samples obtained from 150 individuals for each population. Genotyping of - 3279T> G in the phenobarbital-responsive enhancer module, TA repeats in the TATA box, 211G> A (G71R) and 686C> A (P229Q) in exon 1, and three single nucleotide polymorphisms ( SNPs) (1813C> T, 1941C> G, and 2042C> G) in the 3'-untranslated region in exon 5 was performed. Eight haplotypes of block 1 ( exon 1 and its 5'-flanking region) harboring the first four variations were assigned to each individual. The dominant haplotype for African-Americans was * 28b ( - 3279G; TA(7); 211G; 686C) (0.446), whereas that for the Japanese was * 1a ( - 3279T; TA(6); 211G; 686C) (0.610). Frequencies of the two haplotypes * 1a and * 28b were comparable in Caucasians. Haplotype * 6a (- 3279T; TA(6); 211A; 686C) was characteristic of the Japanese, whereas haplotypes 36b and * 37b ( - 3279T; TA(5) and TA(8); 211G; 686C) were found mostly in African-Americans. Although the three SNPs in block 2 (exons 2 - 5) were in complete linkage in the Japanese, they were not completely linked in African-Americans or Caucasians. These differences in haplotype distribution patterns among the three populations suggest the possibility of ethnic differences in toxicity profiles of drugs detoxicated by UGT1A1. A novel SNP, 686C> T ( P229L), was found in an African-American. The intrinsic clearance of 7-ethyl-10-hydroxycamptothecin (SN-38) by P229L UGT1A1 expressed in COS-1 cells was about 3% of the wild type. The results of Western blotting and real-time reverse transcription-polymerase chain reaction suggest that the low glucuronidation activity of the variant was partly due to its low stability. The variation 686C> T may cause high toxicity during 7-ethyl-10-[4-(1-piperidino)-1-piperidino] carbonyloxycamptothecin (CPT-11) therapy or hyperbilirubinemia in patients.