Pharmacogenetics最新文献

{"title":"Identification of a novel variant CYP2C9 allele in Chinese.","authors":"Dayong Si,&nbsp;Yingjie Guo,&nbsp;Yifan Zhang,&nbsp;Lei Yang,&nbsp;Hui Zhou,&nbsp;Dafang Zhong","doi":"10.1097/01.fpc.0000114749.08559.e4","DOIUrl":"https://doi.org/10.1097/01.fpc.0000114749.08559.e4","url":null,"abstract":"<p><strong>Objectives: </strong>Cytochrome P450 (CYP) 2C9 metabolizes about 16% of drugs in current clinical use, including lornoxicam and tolbutamide. SNPs in the CYP2C9 gene have increasingly been recognized as determinants of the metabolic phenotype that underlies interindividual and ethnic differences.</p><p><strong>Methods: </strong>The present study focused on a Chinese poor metabolizer (PM) whose apparent genotype (CYP2C9*1/CYP2C9*3) did not agree with his PM phenotype for both lornoxicam and tolbutamide. By sequencing his CYP2C9 gene, we identified a new variant CYP2C9 allele involving a T269C transversion in exon 2 that leads to a Leu90Pro substitution in the encoded protein.</p><p><strong>Results: </strong>The CYP2C9 genotype analysis in the family of the poor metabolizer showed the new exon 2 change and CYP2C9*3 occurred on different alleles. Thus, the PM status of this subject could be attributed to his being heterozygous for the CYP2C9 T269C allele together with the CYP2C9*3. Frequency analysis in 147 unrelated Chinese males indicated approximately 2% of the Chinese population carry the allele.</p><p><strong>Conclusion: </strong>This study suggests that this novel CYP2C9 allele was correlated with reduced plasma clearance of drugs that are substrates for CYP2C9.</p>","PeriodicalId":19917,"journal":{"name":"Pharmacogenetics","volume":"14 7","pages":"465-9"},"PeriodicalIF":0.0,"publicationDate":"2004-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1097/01.fpc.0000114749.08559.e4","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"24592296","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Chromosomal aberrations in workers exposed to low levels of benzene: association with genetic polymorphisms.","authors":"Su Young Kim,&nbsp;Jung Keun Choi,&nbsp;Yoon Hee Cho,&nbsp;Eun Jung Chung,&nbsp;Domyung Paek,&nbsp;Hai Won Chung","doi":"10.1097/01.fpc.0000114751.08559.7b","DOIUrl":"https://doi.org/10.1097/01.fpc.0000114751.08559.7b","url":null,"abstract":"<p><p>Benzene and its metabolites damage human lymphocytes, resulting in chromosomal aberrations and aneuploidy. Polymorphisms in the genes for benzene-metabolizing enzymes have been implicated in benzene-associated haematotoxicity. In this study, we examined the specificity of benzene-induced aneuploidy and the influence of genetic polymorphisms (GSTM1, GSTT1, GSTP1, NAT2, NQO1 and CYP2E1) on chromosomal aberrations. In total, 82 benzene-exposed workers from a coke oven plant and 76 matched controls were examined. The benzene concentration in the work-place air ranged from 0.014-0.743 p.p.m. (geometric mean 0.557 p.p.m.). Benzene exposure was associated with significant increases in both monosomy and trisomy of chromosomes 8 and 21. Translocations between chromosomes 8 and 21 [t(8:21)] were eight-fold more frequent in the high-level exposure group compared to the control group. Multiple regression analysis indicated that the frequencies of chromosome aberrations were significantly associated with benzene exposure and polymorphisms in the metabolic enzyme genes. A particular subset of genotypes, which included the GSTM1-null and GSTT1-null genotypes, the slow acetylator type of NAT2, a variant of the NQO1 genotype and the CYP2E1 DraI and RsaI genotypes, were either separately, or in combination, associated with increased frequencies of aneuploidy among the benzene-exposed individuals after adjustments for age, alcohol consumption and smoking. These results suggest that polymorphisms in the genes for benzene-metabolizing enzymes influence the susceptibility of individuals to chromosomal aberrations in relation to benzene exposure.</p>","PeriodicalId":19917,"journal":{"name":"Pharmacogenetics","volume":"14 7","pages":"453-63"},"PeriodicalIF":0.0,"publicationDate":"2004-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1097/01.fpc.0000114751.08559.7b","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"24592295","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mutations in the SLCO1B3 gene affecting the substrate specificity of the hepatocellular uptake transporter OATP1B3 (OATP8).","authors":"Katrin Letschert,&nbsp;Dietrich Keppler,&nbsp;Jörg König","doi":"10.1097/01.fpc.0000114744.08559.92","DOIUrl":"https://doi.org/10.1097/01.fpc.0000114744.08559.92","url":null,"abstract":"<p><strong>Objective: </strong>Hepatocellular uptake transporters are involved in the hepatobiliary elimination of endogenous and xenobiotic substances. Mutations in genes encoding these uptake transporters may be key determinants of interindividual variability in hepatobiliary elimination and drug disposition. Our aim was to investigate the functional consequences of mutations in the SLCO1B3 gene encoding the hepatic uptake transporter for organic anions OATP1B3, formerly termed OATP8.</p><p><strong>Methods: </strong>Mutations occurring in Caucasian Europeans and observed in databases were introduced into the SLCO1B3 cDNA and the consequences were analyzed in stably transfected canine MDCKII cells and human HEK293 cells. The functional consequences were examined for two frequent polymorphisms SLCO1B3-334T>G, encoding OATP1B3-S112A (allelic frequency of 74%) and SLCO1B3-699G>A, encoding OATP1B3-M233I (allelic frequency of 71%) and one rare polymorphism SLCO1B3-1564G>T, encoding OATP1B3-G522C (allelic frequency of 1.9%) and one artificial mutation SLCO1B3-1748G>A, encoding OATP1B3-G583E.</p><p><strong>Results: </strong>OATP1B3-S112A, OATP1B3-M233I, and the OATP1B3 protein corresponding to the reference sequence (accession NM_019844), showed a comparable lateral localization in stably transfected MDCKII cells, whereas OATP1B3-G522C and OATP1B3-G583E proteins were retained intracellularly. Both latter amino acid substitutions abolished the transport of bile acids mediated by OATP1B3, whereas other substrates, like bromosulfophthalein, were transported by all polymorphic variants of the protein.</p><p><strong>Conclusions: </strong>The functional consequences of three polymorphisms and one artificial mutation include differences in the localization and in transport characteristics of several OATP1B3 proteins. This study demonstrates the importance of the analysis of genetic variations in genes encoding transport proteins for the understanding of individual variations in the hepatobiliary elimination of substances.</p>","PeriodicalId":19917,"journal":{"name":"Pharmacogenetics","volume":"14 7","pages":"441-52"},"PeriodicalIF":0.0,"publicationDate":"2004-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1097/01.fpc.0000114744.08559.92","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"24592294","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Identification of the major promoter and non-coding exons of the human arylamine N-acetyltransferase 1 gene (NAT1).","authors":"Anwar Husain,&nbsp;David F Barker,&nbsp;J Christopher States,&nbsp;Mark A Doll,&nbsp;David W Hein","doi":"10.1097/01.fpc.0000114755.08559.6e","DOIUrl":"https://doi.org/10.1097/01.fpc.0000114755.08559.6e","url":null,"abstract":"<p><p>Some carcinogens that initiate rat mammary cancer are substrates of human N-acetyltransferase 1 (NAT1) and variation in NAT1 activity due to environmental or genetic causes may influence human susceptibility to breast cancer. One unexplored potential cause of NAT1 expression variation is polymorphism of transcriptional control sequences. However, the location of the major NAT1 transcription control site is uncertain because earlier publications and current databases report different cDNA structures. To resolve this discrepancy, we used CAP-dependent cDNA cloning to identify 5' ends of NAT1 mRNAs from breast and MCF-7, a mammary adenocarcinoma cell line. Most transcription initiates in a 49-bp region located 11.8 kb upstream of the coding exon. A 79-bp exon located 2.5 kb upstream of the coding exon was found in all 41 of the independent NAT1 cDNA products. Seven of these 41 cDNAs also included other non-coding exons. The structures of NAT1 cDNAs in public databases, as obtained from diverse tissues, reflect a transcription pattern similar to that demonstrated in breast and MCF-7. Genomic fragments spanning the major start region were cloned into a luciferase vector and expressed in MCF-7. Promoter activities were 190-490-fold higher than the vector control and 30-80-fold higher than for a fragment immediately upstream of the coding exon. Our results demonstrate that, in breast, and likely also in other tissues, the major NAT1 mRNA is transcribed from a strong promoter located 11.8 kb upstream of the translated exon, and the mature spliced mRNA includes at least one additional non-coding exon.</p>","PeriodicalId":19917,"journal":{"name":"Pharmacogenetics","volume":"14 7","pages":"397-406"},"PeriodicalIF":0.0,"publicationDate":"2004-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1097/01.fpc.0000114755.08559.6e","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"24592290","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Comprehensive analysis of thiopurine S-methyltransferase phenotype-genotype correlation in a large population of German-Caucasians and identification of novel TPMT variants.","authors":"Elke Schaeffeler,&nbsp;Christine Fischer,&nbsp;Dierk Brockmeier,&nbsp;Dorothee Wernet,&nbsp;Klaus Moerike,&nbsp;Michel Eichelbaum,&nbsp;Ulrich M Zanger,&nbsp;Matthias Schwab","doi":"10.1097/01.fpc.0000114745.08559.db","DOIUrl":"https://doi.org/10.1097/01.fpc.0000114745.08559.db","url":null,"abstract":"<p><p>The thiopurine S-methyltransferase (TPMT) genetic polymorphism has a significant clinical impact on the toxicity of thiopurine drugs. It has been proposed that the identification of patients who are at high risk for developing toxicity on the basis of genotyping could be used to individualize drug treatment. In the present study, phenotype-genotype correlation of 1214 healthy blood donors was investigated to determine the accuracy of genotyping for correct prediction of different TPMT phenotypes. In addition, the influence of gender, age, nicotine and caffeine intake was examined. TPMT red blood cell activity was measured in all samples and genotype was determined for the TPMT alleles *2 and *3. Discordant cases between phenotype and genotype were systematically sequenced. A clearly defined trimodal frequency distribution of TPMT activity was found with 0.6% deficient, 9.9% intermediate and 89.5% normal to high methylators. The frequencies of the mutant alleles were 4.4% (*3A), 0.4% (*3C) and 0.2% (*2). All seven TPMT deficient subjects were homozygous or compound heterozygous carriers for these alleles. In 17 individuals with intermediate TPMT activity discordant to TPMT genotype, four novel variants were identified leading to amino acid changes (K119T, Q42E, R163H, G71R). Taking these new variants into consideration, the overall concordance rate between TPMT genetics and phenotypes was 98.4%. Specificity, sensitivity and the positive and negative predictive power of the genotyping test were estimated to be higher than 90%. Thus, the results of this study provide a solid basis to predict TPMT phenotype in a Northern European Caucasian population by molecular diagnostics.</p>","PeriodicalId":19917,"journal":{"name":"Pharmacogenetics","volume":"14 7","pages":"407-17"},"PeriodicalIF":0.0,"publicationDate":"2004-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1097/01.fpc.0000114745.08559.db","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"24592291","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"CYP3A5*1-carrying graft liver reduces the concentration/oral dose ratio of tacrolimus in recipients of living-donor liver transplantation.","authors":"Maki Goto,&nbsp;Satohiro Masuda,&nbsp;Tetsuya Kiuchi,&nbsp;Yasuhiro Ogura,&nbsp;Fumitaka Oike,&nbsp;Masahiro Okuda,&nbsp;Koichi Tanaka,&nbsp;Ken-ichi Inui","doi":"10.1097/01.fpc.0000114747.08559.49","DOIUrl":"https://doi.org/10.1097/01.fpc.0000114747.08559.49","url":null,"abstract":"<p><strong>Objectives: </strong>Tacrolimus is widely used for immunosuppressive therapy after organ transplantation, but its pharmacokinetics shows such great interindividual variation that control of its blood concentration is difficult. We have previously reported that an intestinal P-glycoprotein (MDR1) contributes to this variation as an absorptive barrier, but the role of hepatic metabolism is not clear.</p><p><strong>Methods: </strong>In this study, we have evaluated the genotypes of MDR1 and cytochrome P450 (CYP) 3A in donor and recipient, and the influence of polymorphisms on mRNA expression and the tacrolimus concentration/dose (C/D) ratio in recipients of living-donor liver transplantation (LDLT).</p><p><strong>Results: </strong>The expression level of MDR1 and tacrolimus C/D ratio were not affected by either MDR1 C3435T or G2677T/A. The CYP3A4*1B genotype was not detected, but the CYP3A5*3 genotype had an allelic frequency of 76.3%. The mRNA level of CYP3A5 was significantly reduced by the *3/*3 genotype, and the tacrolimus C/D ratio was decreased in recipients engrafted with partial liver carrying CYP3A5*1/*1 genotype. An analysis of the combination of intestinal MDR1 level and liver CYP3A5 genotype revealed that the tacrolimus C/D ratio was lower in the group with higher MDR1 levels regardless of CYP3A5 genotype during postoperative week 1.</p><p><strong>Conclusions: </strong>These results indicate that in recipients of LDLT, the pharmacokinetics of tacrolimus is influenced by flux via P-glycoprotein in the intestine during the first week; after that, it is mostly the hepatic metabolism that contributes to the excretion of tacrolimus, and carriers of the CYP3A5*1/*1 genotype require a high dose of tacrolimus to achieve the target concentration.</p>","PeriodicalId":19917,"journal":{"name":"Pharmacogenetics","volume":"14 7","pages":"471-8"},"PeriodicalIF":0.0,"publicationDate":"2004-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1097/01.fpc.0000114747.08559.49","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"24591565","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Closing the gap between science and clinical practice: the thiopurine S-methyltransferase polymorphism moves forward.","authors":"Eugene Y Krynetskiy,&nbsp;William E Evans","doi":"10.1097/01.fpc.0000114753.08559.e9","DOIUrl":"https://doi.org/10.1097/01.fpc.0000114753.08559.e9","url":null,"abstract":"","PeriodicalId":19917,"journal":{"name":"Pharmacogenetics","volume":"14 7","pages":"395-6"},"PeriodicalIF":0.0,"publicationDate":"2004-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1097/01.fpc.0000114753.08559.e9","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"24592289","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Polymorphic NF-Y dependent regulation of human nicotine C-oxidase (CYP2A6).","authors":"Oliver von Richter,&nbsp;Marià Pitarque,&nbsp;Cristina Rodríguez-Antona,&nbsp;Anna Testa,&nbsp;Roberto Mantovani,&nbsp;Mikael Oscarson,&nbsp;Magnus Ingelman-Sundberg","doi":"10.1097/00008571-200406000-00006","DOIUrl":"https://doi.org/10.1097/00008571-200406000-00006","url":null,"abstract":"<p><strong>Objectives: </strong>In humans, cytochrome P450 2A6 (CYP2A6) constitutes the principal nicotine C-oxidase. Several different polymorphic CYP2A6 gene variants are known which contribute to the highly variable expression of this enzyme among individuals. In this study we report a novel polymorphism located in the 5' flanking region (-745A > G) of the CYP2A6 gene disrupting a CCAAT box.</p><p><strong>Methods and results: </strong>Electrophoretic mobility shift assays (EMSA) indicated that NF-YA is part of this nuclear protein complex. Chromatin immunoprecipitation revealed that NF-Y recognizes a region of the CYP2A6 5' flanking region located between -932 and -606. EMSA showed that out of the three CCAAT boxes in the CYP2A6 promoter, with CCAAT core sequences located between -839/-835, -748/-744, and -689/-685, only the one at -748/-744 was able to compete with the nuclear protein complex binding to the -748/-744 CCAAT box. Cotransfection experiments indicated that NF-Y acts as a positive regulatory element on CYP2A6 gene regulation. EMSA demonstrated that an NF-Y consensus oligonucleotide but not the -745A > G oligonucleotide competed efficiently with binding of the protein complex to the -748/-744 CCAAT box. Promoter activity of the -745A > G variant was significantly reduced to 78% relative to the wild-type allele in HepG2 cells transfected with luciferase reporter plasmids. Finally, haplotype analysis was carried out comprising the -745A > G variant in combination with all known CYP2A6 3' and 5' flanking single nucleotide polymorphisms: -1013A > G, -48T > G, and the CYP2A6/CYP2A7 3' flank conversion.</p><p><strong>Conclusion: </strong>A new haplotype, CYP2A6*1H was identified, with allele frequencies of 3.1% in Swedish and 5.2% in Turkish populations.</p>","PeriodicalId":19917,"journal":{"name":"Pharmacogenetics","volume":"14 6","pages":"369-79"},"PeriodicalIF":0.0,"publicationDate":"2004-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1097/00008571-200406000-00006","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"24609826","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Modulation of multidrug resistance P-glycoprotein 1 (ABCB1) expression in human heart by hereditary polymorphisms.","authors":"Konrad Meissner,&nbsp;Gabriele Jedlitschky,&nbsp;Henriette Meyer zu Schwabedissen,&nbsp;Peter Dazert,&nbsp;Lothar Eckel,&nbsp;Silke Vogelgesang,&nbsp;Rolf W Warzok,&nbsp;Michael Böhm,&nbsp;Christian Lehmann,&nbsp;Michael Wendt,&nbsp;Ingolf Cascorbi,&nbsp;Heyo K Kroemer","doi":"10.1097/00008571-200406000-00007","DOIUrl":"https://doi.org/10.1097/00008571-200406000-00007","url":null,"abstract":"<p><strong>Objectives: </strong>Variable expression of the ABC-type multidrug resistance membrane protein P-glycoprotein (P-gp, MDR1, ABCB1) in human heart is a potential modulator of drug effects or drug-induced cardiotoxicity. Expression of P-gp is known to be affected by single nucleotide polymorphisms in the MDR1 gene. Therefore, genotype-dependent expression of P-gp could be an important modulator of action of cardiac drugs.</p><p><strong>Methods: </strong>Heart tissue (auriculum) from 51 patients undergoing coronary artery bypass graft surgery was screened for genotype-dependent P-gp expression. P-gp was identified by immunoblotting and localized using immunohistochemistry. MDR1 mRNA was quantified by real-time PCR and immunohistochemistry and related to the MDR1 genotypes G2677T/A (Ala893Ser/Thr) and C3435T.</p><p><strong>Results: </strong>MDR1/18S rRNA mRNA copy numbers in heart auriculum were 3.48 +/- 2.25 x 10(-6) compared to 4.56 +/- 0.58 x 10(-6) in non-failing ventricular samples studied before. While the exon 26 C3435T genotype did not influence MDR1 mRNA expression, we found significantly elevated MDR1 mRNA expression in 10 patients carrying the exon 21 2677 AT or TT genotype as compared to 12 patients carrying the GG-variant with intermediate MDR1 mRNA expression in 29 heterozygous samples. P-gp was detected in the endothelial wall. Quantitative immunohistochemistry of protein expression, however, did not reveal significant influence of the studied SNPs.</p><p><strong>Conclusion: </strong>The present study based on auricular samples suggests that genetic factors play a rather limited role in modulating P-gp expression in human heart. Therefore, the substantial interindividual variability in cardiac P-gp expression is likely related to environmental or disease related factors.</p>","PeriodicalId":19917,"journal":{"name":"Pharmacogenetics","volume":"14 6","pages":"381-5"},"PeriodicalIF":0.0,"publicationDate":"2004-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1097/00008571-200406000-00007","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"24609827","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Polymorphism of human mu class glutathione transferases.","authors":"Natasha Tetlow,&nbsp;Anna Robinson,&nbsp;Tim Mantle,&nbsp;Philip Board","doi":"10.1097/00008571-200406000-00005","DOIUrl":"https://doi.org/10.1097/00008571-200406000-00005","url":null,"abstract":"<p><strong>Objectives and methods: </strong>A combined database mining approach was used to detect polymorphisms in the mu class glutathione-S-transferase (GST) genes. Although a large number of potential polymorphisms were detected in the five genes that comprise the Mu class GSTs using sequence alignment programs and by searching single nucleotide polymorphism databases, the majority were not validated or detected in three major ethnic populations (African, Southern Chinese and Australian European).</p><p><strong>Results: </strong>Two new polymorphisms were detected and characterized in the GSTM3 gene. A rare pG147W substitution was detected only in the Southern Chinese subjects. A more common pV224I substitution was found in each of the ethnic groups studied, and significant differences in allele frequencies were observed between each group. These two polymorphisms can combine to form four distinct haplotypes (GSTM3A [p.G147;V224], GSTM3C [p.G147;I224], GSTM3D [p.W147;V224], GSTM3E [p.W147;I224]). The four isoforms were expressed in Escherichia coli and characterized enzymatically with several substrates including 1-chloro-2,4-dinitrobenzene (CDNB), cumene hydroperoxide and t-nonenal. GSTM3-3 containing the variant p.W147 residue tended to show diminished specific activity and catalytic efficiency with CDNB. In contrast, GSTM3-3 containing the variant p.I224 residue tended to show increased specific activity and catalytic efficiency with CDNB. Interactions between the different p.147 and p.224 residues were also observed, with the GSTM3C isoform exhibiting the greatest activity with each substrate, and GSTM3E the lowest.</p><p><strong>Conclusion: </strong>These functional polymorphisms may play a significant role in modulating the ability of GSTM3-3 to metabolize substrates such as the chemotherapeutic agent 1,3-bis(2-chloroethyl)-1-nitrosourea.</p>","PeriodicalId":19917,"journal":{"name":"Pharmacogenetics","volume":"14 6","pages":"359-68"},"PeriodicalIF":0.0,"publicationDate":"2004-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1097/00008571-200406000-00005","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"24609825","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}