Abstract
Ethnic differences in genetic polymorphisms in UDP-glucuronosyltransferase 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;TA7; 211G;686C) (0.446), whereas that for the Japanese was *1a (–3279T; TA6;211G;686C) (0.610). Frequencies of the two haplotypes *1a and *28b were comparable in Caucasians. Haplotype *6a (–3279T;TA6; 211A;686C) was characteristic of the Japanese, whereas haplotypes *36b and *37b (–3279T;TA5 and TA8;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.
Footnotes
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This study was supported in part by the program for the Promotion of Studies in Health Sciences of the Ministry of Health, Labor and Welfare and the program for the Promotion of Fundamental Studies in Health Sciences of the Pharmaceuticals and Medical Devices Agency of Japan.
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Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.
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doi:10.1124/dmd.104.001800.
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ABBREVIATIONS: SN-38, 7-ethyl-10-hydroxycamptothecin; CPT-11, 7-ethyl-10-[4-(1-piperidino)-1-piperidino]carbonyloxycamptothecin; SN-38G, 7-ethyl-10-hydroxycamptothecin glucuronide; CN, Crigler-Najjar; SNP, single nucleotide polymorphism; PCR, polymerase chain reaction; RT-PCR, reverse transcription-polymerase chain reaction.
- Received August 10, 2004.
- Accepted November 23, 2004.
- The American Society for Pharmacology and Experimental Therapeutics
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