Pharmacogenetics最新文献

{"title":"HLA-B*5701 and abacavir hypersensitivity.","authors":"Maria E Watson, Jeanne M Pimenta, William R Spreen, Jaime E Hernandez","doi":"10.1097/00008571-200411000-00011","DOIUrl":"https://doi.org/10.1097/00008571-200411000-00011","url":null,"abstract":"","PeriodicalId":19917,"journal":{"name":"Pharmacogenetics","volume":"14 11","pages":"783-4; author reply 784"},"PeriodicalIF":0.0,"publicationDate":"2004-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1097/00008571-200411000-00011","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"24832873","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":"Functional analysis of single nucleotide polymorphisms of hepatic organic anion transporter OATP1B1 (OATP-C).","authors":"Megumi Iwai,&nbsp;Hiroshi Suzuki,&nbsp;Ichiro Ieiri,&nbsp;Kenji Otsubo,&nbsp;Yuichi Sugiyama","doi":"10.1097/00008571-200411000-00006","DOIUrl":"https://doi.org/10.1097/00008571-200411000-00006","url":null,"abstract":"<p><strong>Objective: </strong>Two kinds of single nucleotide polymorphism (SNP; Asn130Asp and Val174Ala) are frequently observed in the liver specific transporter, organic anion transporting polypeptide 1B1 (OATP1B1/OATP-C) gene. Although these two SNPs occur independently in European-Americans, Val174Ala is mostly associated with Asn130Asp in Japanese. Our previous in-vivo studies in Japanese subjects indicated that the non-renal clearance of pravastatin was decreased to 13% of that in wild-type subjects (Nishizato et al. Clin Pharmacol Ther 2003;73(6):554-564). The purpose of the present study is to characterize the function of SNPs variants of OATP1B1 in cDNA transfected cells.</p><p><strong>Methods: </strong>The localization and transport activity were analyzed in HEK293 cells stably expressing wild-type OATP1B1 (OATP1B1*1a), OATP1B1*1b (Asn130Asp), OATP1B1*5 (Val174Ala) and OATP1B1*15 (Asn130Asp and Val174Ala). To characterize the intrinsic Vmax, observed Vmax in uptake study were normalized by the expression level estimated from Western blotting.</p><p><strong>Results: </strong>All SNP variants are predominantly located on the cell surface. No significant alteration was observed in Km values for the transport of 17beta-estradiol 17beta-d-glucuronide (E217betaG), a typical substrate of OATP1B1, among these SNP variants. However, the normalized Vmax value for OATP1B1*15 was drastically decreased to less than 30% compared with OATP1B1*1a. In contrast, the transport activity of OATP1B1*1b (Asn130Asp) and OATP1B1*5 (Val 174Ala) was similar to that of OATP1B1*1a.</p><p><strong>Conclusions: </strong>These results are consistent with the results of our previous clinical studies. It is thus suggested that in-vivo disposition may be predicted from in-vitro results using recombinant transporters.</p>","PeriodicalId":19917,"journal":{"name":"Pharmacogenetics","volume":"14 11","pages":"749-57"},"PeriodicalIF":0.0,"publicationDate":"2004-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1097/00008571-200411000-00006","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"24832980","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":"Regulation of CYP3A4 by the bile acid receptor FXR: evidence for functional binding sites in the CYP3A4 gene.","authors":"Carmela Gnerre,&nbsp;Sharon Blättler,&nbsp;Michel R Kaufmann,&nbsp;Renate Looser,&nbsp;Urs A Meyer","doi":"10.1097/00008571-200410000-00001","DOIUrl":"https://doi.org/10.1097/00008571-200410000-00001","url":null,"abstract":"<p><p>CYP3A4, the most abundant cytochrome P450 in human liver, is responsible for the metabolism of numerous xenobiotics and endobiotics. CYP3A4 expression is highly variable and is induced by numerous compounds of exogenous and endogenous origin, including elevated concentrations of secondary bile acids via the pregnane X receptor (PXR). We show that physiological concentrations of the primary bile acid chenodeoxycholic acid regulate the expression of CYP3A4 via the bile acid receptor FXR. Experiments performed in vitro in different cell culture systems, gel-mobility shift assays and experiments performed in vivo in transgenic mice lacking FXR or PXR and treated with the synthetic FXR agonist GW4064 were undertaken to study the implication of FXR in the regulation of CYP3A. Our data provide evidence for the presence of two functional FXR recognition sites located in a 345-bp element within the 5'-flanking region of CYP3A4. Mutational analysis of these sites and experiments in transgenic mice lacking FXR or PXR support the relevance of FXR activation for CYP3A regulation. Thus, whereas elevated concentrations of precursors of bile acids and secondary bile acids induce CYP3A via PXR, primary bile acids can modulate the expression of CYP3A via FXR. These findings may explain elevated CYP3A expression in cholestasis and part of the variability of drug responsiveness and toxicity between individuals.</p>","PeriodicalId":19917,"journal":{"name":"Pharmacogenetics","volume":"14 10","pages":"635-45"},"PeriodicalIF":0.0,"publicationDate":"2004-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1097/00008571-200410000-00001","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"24763664","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 deletion-junction site of CYP2A6*4B allele lacking entire coding region of CYP2A6 in Japanese.","authors":"Noritaka Ariyoshi,&nbsp;Hiromi Sekine,&nbsp;Kazuo Nakayama,&nbsp;Katsuhiko Saito,&nbsp;Atsushi Miyamoto,&nbsp;Tetsuya Kamataki","doi":"10.1097/00008571-200410000-00008","DOIUrl":"https://doi.org/10.1097/00008571-200410000-00008","url":null,"abstract":"","PeriodicalId":19917,"journal":{"name":"Pharmacogenetics","volume":"14 10","pages":"701-5"},"PeriodicalIF":0.0,"publicationDate":"2004-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1097/00008571-200410000-00008","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"24763669","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":"The effect of variable CYP3A5 expression on cyclosporine dosing, blood pressure and long-term graft survival in renal transplant patients.","authors":"Reinhold Kreutz,&nbsp;Heiko Zürcher,&nbsp;Silke Kain,&nbsp;Peter Martus,&nbsp;Gerd Offermann,&nbsp;Joachim Beige","doi":"10.1097/00008571-200410000-00004","DOIUrl":"https://doi.org/10.1097/00008571-200410000-00004","url":null,"abstract":"<p><strong>Objective: </strong>Cyclosporine is extensively metabolized by cytochrome-P450 3A (CYP3A) enzymes in the liver and intestine including the CYP3A5 isoenzyme. CYP3A5 is also expressed in the kidney and has been implicated in blood pressure regulation. Appreciable expression of CYP3A5 occurs in carriers of the CYP3A5*1 allele, while the CYP3A5*3 allele is associated with low expression. We tested whether the presence of the CYP3A5*1 allele in renal transplant recipients and in donor kidneys influences cyclosporine dose requirements, blood pressure and long-term graft survival in renal transplant patients during chronic treatment with a cyclosporine-based immunosuppressive regimen.</p><p><strong>Methods: </strong>We studied 399 Caucasian patients from our single-center registry with stable graft function for more than 10 weeks after transplantation. The genotypes for CYP3A5*1/*3 were determined by a TaqMan PCR method. Cyclosporine dose requirements, blood pressure and graft survival were analyzed in relation to the presence or absence of the CYP3A5*1 allele in recipients and donor kidneys.</p><p><strong>Results: </strong>The CYP3A5*1 allele was found in 15.5% of the recipients and in 11.8% of the donor kidneys. The recipient CYP3A5*1 allele had no effect on cyclosporine dose and blood concentrations at trough with and without dose-adjustment. Blood pressure, number of antihypertensive compounds used for treatment and graft survival evaluated by Kaplan-Meier curves and Cox regression analysis were also not affected by the CYP3A5*1 allele either in recipients or donor kidneys.</p><p><strong>Conclusions: </strong>Cyclosporine dose requirements, blood pressure and long-term renal graft survival are not influenced by the CYP3A5*1 allele in Caucasian patients.</p>","PeriodicalId":19917,"journal":{"name":"Pharmacogenetics","volume":"14 10","pages":"665-71"},"PeriodicalIF":0.0,"publicationDate":"2004-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1097/00008571-200410000-00004","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"24763665","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":"Increased levels of aflatoxin-albumin adducts are associated with CYP3A5 polymorphisms in The Gambia, West Africa.","authors":"Leszek Wojnowski,&nbsp;Paul C Turner,&nbsp;Bonnie Pedersen,&nbsp;Elisabeth Hustert,&nbsp;Jürgen Brockmöller,&nbsp;Maimuna Mendy,&nbsp;Hilton C Whittle,&nbsp;Greg Kirk,&nbsp;Christopher P Wild","doi":"10.1097/00008571-200410000-00007","DOIUrl":"https://doi.org/10.1097/00008571-200410000-00007","url":null,"abstract":"<p><strong>Objectives: </strong>Major risk factors for hepatocellular carcinoma (HCC) are hepatitis viruses and exposure to aflatoxins, including aflatoxin B1 (AFB1). The mutagenic effect of AFB1 results from hepatic bioactivation to AFB1-exo-8,9-epoxide. This is in part catalysed by CYP3A5, an enzyme expressed polymorphically. We investigated the role of CYP3A5 polymorphisms in the formation of AFB1-exo-8,9-epoxide in The Gambia, a population exposed to high aflatoxin levels.</p><p><strong>Methods: </strong>Common CYP3A5 polymorphisms were identified in an African-American population. Subsequently, 288 Gambian subjects were genotyped and CYP3A5 activity predicted using haplotypes of the three variant loci (CYP3A5*3, *6 and *7) associated with decreases in protein expression. CYP3A5 expression was then compared to aflatoxin-albumin (AF-alb) adduct, a biomarker of AFB1 bioactivation; data were also analysed in relation to expression of other aflatoxin-metabolizing enzymes.</p><p><strong>Results: </strong>CYP3A5 haplotypes reflecting high CYP3A5 protein expression were associated with increased AF-alb. Compared to individuals with predicted low expression those predicted to express CYP3A5 from one allele displayed 16.1% higher AF-alb (95% CI: -2.5, 38.2, P = 0.093) and homozygous expressers displayed 23.2% higher AF-alb levels (95% CI: -0.01, 52.0, P = 0.051). The effect of the CYP3A5 polymorphism was strongest in individuals with low CYP3A4 activity with a 70.1% increase in AF-alb (95% CI: 11.8, 158.7, P < 0.05) in high compared to low expressers. A similar effect was observed for individuals with null alleles of GSTM1, which conjugates the AFB1-exo-8,9-epoxide to reduced glutathione.</p><p><strong>Conclusions: </strong>The CYP3A5 polymorphism is associated with increased levels of the mutagenic AFB1-exo-8,9-epoxide, particularly in individuals with low CYP3A4, and this may modulate individual risk of HCC.</p>","PeriodicalId":19917,"journal":{"name":"Pharmacogenetics","volume":"14 10","pages":"691-700"},"PeriodicalIF":0.0,"publicationDate":"2004-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1097/00008571-200410000-00007","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"24763668","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 and characterization of the FMO2 gene in Rattus norvegicus: a good model to study metabolic and toxicological consequences of the FMO2 polymorphism.","authors":"Marine Hugonnard,&nbsp;Etienne Benoit,&nbsp;Christiane Longin-Sauvageon,&nbsp;Virginie Lattard","doi":"10.1097/00008571-200410000-00002","DOIUrl":"https://doi.org/10.1097/00008571-200410000-00002","url":null,"abstract":"<p><strong>Background: </strong>In lung of many animal species flavin-containing monooxygenase 2 (FMO2) is a 535-amino acid residues drug-metabolizing enzyme. In humans FMO2 exhibits a genetic polymorphism. The major allele encodes a truncated FMO2, the minor allele a full-length FMO2. In laboratory rats we previously reported a FMO2 gene encoding a truncated FMO2 (432-AA residues). In these strains, a double deletion leads to the appearance of a premature stop codon. All laboratory rat strains were derived from the same wild ancestor, Rattus norvegicus.</p><p><strong>Methods: </strong>A PCR-based method able to specifically recognize either the wild-type or the mutant allele was developed to investigate a putative FMO2 polymorphism in a population of wild rats. The FMO2 gene was analyzed in 42 wild rats.</p><p><strong>Results: </strong>A genetic FMO2 polymorphism similar to that described in humans was found in R. norvegicus. We observed three different genotypes: homozygotes for the wild-type FMO2 (33.3%), homozygotes for the mutant FMO2 (38.1%) and heterozygotes (28.6%). Comparative FMO2 mRNA and protein expressions in lungs were studied by reverse transcription-PCR and western blotting. FMO2 mRNA expression was identical between the three groups. In contrast, major differences in the expression of FMO2 protein were detected. FMO2 was strongly expressed in lungs of homozygotes for the wild-type FMO2, faintly expressed in lungs of heterozygotes and non-expressed in lungs of homozygotes for the mutant FMO2. Comparative catalytic properties of lung microsomes were studied by the determination of the oxygenation of methimazole. FMO2 genetic polymorphism was associated with major differences in the S-oxidative metabolism.</p>","PeriodicalId":19917,"journal":{"name":"Pharmacogenetics","volume":"14 10","pages":"647-55"},"PeriodicalIF":0.0,"publicationDate":"2004-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1097/00008571-200410000-00002","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"24762576","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":"A novel CYP2C9 variant that caused erroneous genotyping in a patient on warfarin therapy.","authors":"Rika Okuda,&nbsp;Hiromi Izumoto,&nbsp;Masaki Nishiki,&nbsp;Kayo Matsuura,&nbsp;Keisuke Matsuzaki,&nbsp;Tomoyuki Uemichi,&nbsp;Tomokazu Suzuki","doi":"10.1097/00008571-200410000-00009","DOIUrl":"https://doi.org/10.1097/00008571-200410000-00009","url":null,"abstract":"","PeriodicalId":19917,"journal":{"name":"Pharmacogenetics","volume":"14 10","pages":"707-9"},"PeriodicalIF":0.0,"publicationDate":"2004-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1097/00008571-200410000-00009","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"24763670","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":"Functional polymorphism of human glutathione transferase A3: effects on xenobiotic metabolism and steroid biosynthesis.","authors":"Natasha Tetlow,&nbsp;Marjorie Coggan,&nbsp;Marco G Casarotto,&nbsp;Philip G Board","doi":"10.1097/00008571-200410000-00003","DOIUrl":"https://doi.org/10.1097/00008571-200410000-00003","url":null,"abstract":"<p><p>The alpha class glutathione transferase GSTA3-3 is involved in steroid biosynthesis and the metabolism of some xenobiotics. A bioinformatics approach was utilized to identify novel coding region polymorphisms in the glutathione transferase A3 gene (GSTA3). We describe an I71L polymorphism in GSTA3 that occurs at a low frequency in African populations. The activity of the leucine containing isoform was significantly reduced in a range of glutathione-conjugating reactions due to a diminished affinity for reduced glutathione, indicating that this allele could be implicated in disease caused by oxidative stress in steroidogenic tissue. By contrast, the delta(5)-androsten-3,17-dione isomerase activity of GSTA3-3 was not affected by this substitution, indicating that there is no direct effect on steroid synthesis. However, the L71 isoform displayed diminished stability at 45 degrees C. If this relative instability is mirrored in vivo, testosterone and progesterone synthesis may be affected in individuals carrying this allele.</p>","PeriodicalId":19917,"journal":{"name":"Pharmacogenetics","volume":"14 10","pages":"657-63"},"PeriodicalIF":0.0,"publicationDate":"2004-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1097/00008571-200410000-00003","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"24763663","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":"Association between a polymorphism in cysteinyl leukotriene receptor 2 on chromosome 13q14 and atopic asthma.","authors":"Hiromi Fukai,&nbsp;Yoshino Ogasawara,&nbsp;Ohsuke Migita,&nbsp;Minori Koga,&nbsp;Kunio Ichikawa,&nbsp;Masanao Shibasaki,&nbsp;Tadao Arinami,&nbsp;Emiko Noguchi","doi":"10.1097/00008571-200410000-00006","DOIUrl":"https://doi.org/10.1097/00008571-200410000-00006","url":null,"abstract":"<p><strong>Objective: </strong>Cysteinyl leukotriene receptor 2 (CYSLTR2) is one of the receptors for the cysteinyl leukotrienes (CYSLTs), which cause bronchoconstrictions, vascular hyperpermeability and mucus hypersecretion in asthmatic patients. CYSLTR1 antagonists have been shown to be effective in the treatment of chronic asthma. CYSLTR2 is located approximately 300 kb from D13S153, which is reportedly linked to asthma in several populations. We characterized the genomic structure of humans CYSLTR2, determined the putative major promoter region and conducted association studies pertaining to polymorphisms in CYSLTR2 and asthma.</p><p><strong>Methods and results: </strong>We identified three novel exons in the 5' untranslated region of CYSLTR2 by rapid amplification of cDNA ends and identified eight novel polymorphisms in CYSLTR2 by direct sequencing. A transmission disequilibrium test with 137 Japanese asthmatic families revealed that the -1220A > C polymorphism is associated with the development of asthma (P = 0.0066). In addition, a polymorphism in the putative promoter region caused different promoter activities in vitro.</p><p><strong>Conclusion: </strong>Our results suggest that CYSLTR2 is one of the genes that contributes to susceptibility to asthma in the Japanese population.</p>","PeriodicalId":19917,"journal":{"name":"Pharmacogenetics","volume":"14 10","pages":"683-90"},"PeriodicalIF":0.0,"publicationDate":"2004-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1097/00008571-200410000-00006","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"24763667","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}