Racial variability in haplotype frequencies of UGT1A1 and glucuronidation activity of a novel single nucleotide polymorphism 686C>T (P229L) found in an African-American

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.