TY - JOUR
T1 - Determination and analysis of single nucleotide polymorphisms and haplotype structure of the human carboxylesterase 2 gene
AU - Wu, Michael H.
AU - Chen, Peixian
AU - Wu, Xiaolin
AU - Liu, Wanqing
AU - Strom, Stephen
AU - Das, Soma
AU - Cook, Edwin H.
AU - Rosner, Gary L.
AU - Dolan, M. Eileen
PY - 2004/9
Y1 - 2004/9
N2 - Carboxylesterases are members of the serine esterase super family important in the metabolism of a wide variety of substrates, including xenobiotics and prodrugs. There are two known carboxylesterases expressed in human liver, small intestine and other tissues, carboxylesterase 1 (CES1) and carboxylesterase 2 (CES2). The aim of this study was to identify polymorphisms in the CES2 gene and determine whether these polymorphisms affect expression levels of CES2 or rate of metabolism of irinotecan (7-ethyl-10-[4-(1-piperidino)-1-piperidino] carbonyloxy-camptothecin). Microsome samples prepared from liver tissues of 78 normal individuals were used to determine the rate of hydrolysis of irinotecan and procaine (an anaesthetic hydrolysed by CES2 but not CES1). The rate of hydrolysis of irinotecan is highly variable among individuals, ranging from 2.7-138 pmol/mg protein/h (mean ± SD 26.0 ± 22.9). Fifteen single nucleotide polymorphisms (SNPs) were identified, one is in an exon, 9 are in introns, three are in the 3′-untranslated region (UTR), and two are in the 5′-flanking region. Eight of the 15 SNP loci have rare allele frequencies greater than 5%, of which three were greater than 20%. Genotyping of samples from the SNP Consortium demonstrated different distributions among African-Americans, Asian-Americans and European-Americans. We also analysed the haplotype structure and estimated linkage disequilibrium (LD). A SNP located in the 5′-UTR (5′-UTR-363) was found in LD with loci in intron 1 (Intron1 + 947, Intron1 + 1361, Intron1 + 1643). Haplotypes with homozygous rare alleles on these loci exhibit lower mRNA levels as determined by real time polymerase chain reaction (P < 0.01) and the incorporation of rare alleles in haplotypes correlate with reduced mRNA (P = 0.03). The 5′-UTR-363 SNP is located in one of the three promoters of CES2. However, we did not observe significant differences in CES2 activities (irinotecan and procaine hydrolysis) among individuals with different haplotypes.
AB - Carboxylesterases are members of the serine esterase super family important in the metabolism of a wide variety of substrates, including xenobiotics and prodrugs. There are two known carboxylesterases expressed in human liver, small intestine and other tissues, carboxylesterase 1 (CES1) and carboxylesterase 2 (CES2). The aim of this study was to identify polymorphisms in the CES2 gene and determine whether these polymorphisms affect expression levels of CES2 or rate of metabolism of irinotecan (7-ethyl-10-[4-(1-piperidino)-1-piperidino] carbonyloxy-camptothecin). Microsome samples prepared from liver tissues of 78 normal individuals were used to determine the rate of hydrolysis of irinotecan and procaine (an anaesthetic hydrolysed by CES2 but not CES1). The rate of hydrolysis of irinotecan is highly variable among individuals, ranging from 2.7-138 pmol/mg protein/h (mean ± SD 26.0 ± 22.9). Fifteen single nucleotide polymorphisms (SNPs) were identified, one is in an exon, 9 are in introns, three are in the 3′-untranslated region (UTR), and two are in the 5′-flanking region. Eight of the 15 SNP loci have rare allele frequencies greater than 5%, of which three were greater than 20%. Genotyping of samples from the SNP Consortium demonstrated different distributions among African-Americans, Asian-Americans and European-Americans. We also analysed the haplotype structure and estimated linkage disequilibrium (LD). A SNP located in the 5′-UTR (5′-UTR-363) was found in LD with loci in intron 1 (Intron1 + 947, Intron1 + 1361, Intron1 + 1643). Haplotypes with homozygous rare alleles on these loci exhibit lower mRNA levels as determined by real time polymerase chain reaction (P < 0.01) and the incorporation of rare alleles in haplotypes correlate with reduced mRNA (P = 0.03). The 5′-UTR-363 SNP is located in one of the three promoters of CES2. However, we did not observe significant differences in CES2 activities (irinotecan and procaine hydrolysis) among individuals with different haplotypes.
KW - CES2
KW - Carboxylesterase 2
KW - Haplotype
KW - Linkage disequilibrium
KW - Single nucleotide polymorphism
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U2 - 10.1097/00008571-200409000-00004
DO - 10.1097/00008571-200409000-00004
M3 - Article
C2 - 15475733
AN - SCOPUS:4644275987
VL - 14
SP - 595
EP - 605
JO - Pharmacogenetics and Genomics
JF - Pharmacogenetics and Genomics
SN - 1744-6872
IS - 9
ER -