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-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;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.
Kaniwa
Nahoko
N
Division of Medicinal Safety Science, National Institute of Health Sciences, 1-18-1 Kamiyoga, Setagaya-ku, Tokyo 158-8501, Japan. nkaniwa@nihs.go.jp
Kurose
Kouichi
K
Jinno
Hideto
H
Tanaka-Kagawa
Toshiko
T
Saito
Yoshiro
Y
Saeki
Mayumi
M
Sawada
Jun-Ichi
J
Tohkin
Masahiro
M
Hasegawa
Ryuichi
R
D001741:Black or African American; D000818:Animals; D044466:Asian People; D019556:COS Cells; D002166:Camptothecin / Q000031:analogs & derivatives / Q000378:metabolism; D002522:Chlorocebus aethiops; D005787:Gene Frequency; D020719:Glucuronides / Q000378:metabolism; D014453:Glucuronosyltransferase / Q000235:genetics* / Q000378:metabolism; D006239:Haplotypes; D006801:Humans; D000077146:Irinotecan; D020641:Polymorphism, Single Nucleotide; D012333:RNA, Messenger / Q000096:biosynthesis; D044465:White People; D000099148:UGT1A1 Enzyme
D002166:Camptothecin; D020719:Glucuronides; D014453:Glucuronosyltransferase; D000077146:Irinotecan; D012333:RNA, Messenger; D000099148:UGT1A1 Enzyme