Pharmacogenetics最新文献_第2页

Redefinition of the human kappa opioid receptor gene (OPRK1) structure and association of haplotypes with opiate addiction. 人类卡巴阿片受体基因（OPRK1）结构的重新定义以及单倍型与阿片类药物成瘾的关联。

Pharmacogenetics Pub Date : 2004-12-01 DOI: 10.1097/00008571-200412000-00002

Vadim Yuferov, David Fussell, K Steven LaForge, David A Nielsen, Derek Gordon, Ann Ho, Suzanne M Leal, Jurg Ott, Mary Jeanne Kreek

{"title":"Redefinition of the human kappa opioid receptor gene (OPRK1) structure and association of haplotypes with opiate addiction.","authors":"Vadim Yuferov, David Fussell, K Steven LaForge, David A Nielsen, Derek Gordon, Ann Ho, Suzanne M Leal, Jurg Ott, Mary Jeanne Kreek","doi":"10.1097/00008571-200412000-00002","DOIUrl":"10.1097/00008571-200412000-00002","url":null,"abstract":"The kappa opioid receptor (KOR) plays a role in stress responsivity, opiate withdrawal and responses to cocaine. KOR activation by its endogenous ligand dynorphin A(1-17) decreases basal and drug-induced striatal levels of dopamine. The complete structure of the human KOR gene (hOPRK1) has not been previously determined. This study: (i) characterized the genomic structure of the hOPRK1 gene; (ii) identified single nucleotide polymorphisms (SNPs) in the hOPRK1 gene; and (iii) investigated possible associations of these variants with vulnerability to develop heroin addiction. Analysis of 5'-RACE cDNA clones revealed the presence of a novel exon 1 ranging in length from 167 to 251 nucleotides in the 5' 5'-untranslated region of the hOPRK1 mRNA. We found that the hOPRK1 gene has four major exons and three introns, similar to rodent OPRK1 genes. Direct sequencing of amplified DNA containing all four exons and intron 1 of the hOPRK1 gene were evaluated for polymorphisms in 291 subjects (145 former heroin addicts and 146 controls). Twelve SNPs were identified, nine novel variants and three previously reported SNPs. Using logistic regression with opioid dependence as the dependent variable, the 36G>T SNP exhibited a point-wise significant association (P = 0.016) with disease status. The number of haplotypes seen in the three ethnic groups were nine, six and five for African-Americans, Caucasians, and Hispanics, respectively, with corresponding significance levels for differences in haplotype frequencies between cases and controls of P = 0.0742, 0.1015 and 0.0041. Combining ethnicities by Fisher's method yields an empirical significance level of P = 0.0020.","PeriodicalId":19917,"journal":{"name":"Pharmacogenetics","volume":"14 12","pages":"793-804"},"PeriodicalIF":0.0,"publicationDate":"2004-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6141019/pdf/nihms-988245.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"24868901","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Contribution of common polymorphisms in reduced folate carrier and gamma-glutamylhydrolase to methotrexate polyglutamate levels in patients with rheumatoid arthritis. 类风湿性关节炎患者中叶酸载体和γ -谷氨酰水解酶减少对甲氨蝶呤多谷氨酸水平的共同多态性的贡献

Pharmacogenetics Pub Date : 2004-11-01 DOI: 10.1097/00008571-200411000-00004

Thierry Dervieux, Joel Kremer, Diana Orentas Lein, Robert Capps, Robert Barham, Gary Meyer, Katie Smith, Jacques Caldwell, Daniel E Furst

{"title":"Contribution of common polymorphisms in reduced folate carrier and gamma-glutamylhydrolase to methotrexate polyglutamate levels in patients with rheumatoid arthritis.","authors":"Thierry Dervieux, Joel Kremer, Diana Orentas Lein, Robert Capps, Robert Barham, Gary Meyer, Katie Smith, Jacques Caldwell, Daniel E Furst","doi":"10.1097/00008571-200411000-00004","DOIUrl":"https://doi.org/10.1097/00008571-200411000-00004","url":null,"abstract":"We investigated whether polymorphisms in reduced folate carrier (SLC19A1 G80A) and gamma-glutamyl-hydrolase (GGH-401C/T) are predictive of methotrexate polyglutamate (MTXPG) levels in patients with rheumatoid arthritis treated with weekly low-dose methotrexate (MTX). Adult patients treated with MTX were enrolled in a multicentred study. Blood was drawn at the time of the visit, DNA was extracted and red blood cell (RBC) MTXPG levels (up to the penta-order of glutamation) were measured by high-performance liquid chromatography-fluorometry. A G80A polymorphism in SLC19A1 and a -401C/T promoter polymorphism in GGH were measured by polymerase chain reaction-restriction fragment length polymorphism. Multivariate linear and logistic regressions were used to predict long-chain RBC MTXPG3-5. In 226 adult patients receiving MTX (median 15 mg range: 5-25 mg) median RBC long-chain MTXPG3-5 was 56 nmol/l (range < 5-224 nmol/l). A total of 35 patients carried the SLC19A1 80AA genotype whereas 36 patients carried the GGH-401TT genotype. Weekly MTX dose, age, presence of the SLC19A1 80AA and GGH-401TT genotypes predicted independently and significantly MTXPG3-5 levels (global r = 0.38; P < 0.0001). Patients with the GGH-401TT genotype were 4.8-fold [odds ratio (OR) 95% confidence interval (CI) 1.8-13.0; P = 0.002] more likely to have MTXPG3-5 below the group median compared to patient carriers of the GGH-401CC or CT genotype. Conversely, those with the SLC19A1 80AA genotype were 3.4-fold more likely to have MTXPG3-5 levels above the group median compared to those with the SLC19A1 80GG or 80GA genotype (OR CI 95% 1.4-8.4; P = 0.007). These data demonstrate that polymorphisms in SLC19A1 and GGH affect polyglutamation of MTX.","PeriodicalId":19917,"journal":{"name":"Pharmacogenetics","volume":"14 11","pages":"733-9"},"PeriodicalIF":0.0,"publicationDate":"2004-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1097/00008571-200411000-00004","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"24832978","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}

引用次数: 171

Complex haplotype structure of the human GNAS gene identifies a recombination hotspot centred on a single nucleotide polymorphism widely used in association studies. 人类GNAS基因的复杂单倍型结构确定了一个以单核苷酸多态性为中心的重组热点，广泛用于关联研究。

Pharmacogenetics Pub Date : 2004-11-01 DOI: 10.1097/00008571-200411000-00005

Wanling Yang, Brook White, Eleanor K Spicer, Benjamin L Weinstein, John D Hildebrandt

{"title":"Complex haplotype structure of the human GNAS gene identifies a recombination hotspot centred on a single nucleotide polymorphism widely used in association studies.","authors":"Wanling Yang, Brook White, Eleanor K Spicer, Benjamin L Weinstein, John D Hildebrandt","doi":"10.1097/00008571-200411000-00005","DOIUrl":"https://doi.org/10.1097/00008571-200411000-00005","url":null,"abstract":"The alpha subunit of the heterotrimeric G protein Gs (Gsalpha) is involved in numerous physiological processes and is a primary determinant of cellular responses to extracellular signals. Genetic variations in the Gsalpha gene may play an important role in complex diseases and drug responses. To characterize the genetic diversity in this locus, we resequenced exons and flanking introns of the gene in 44 genomic samples and analysed the haplotype structure of the gene in an additional 50 African-Americans and 50 Caucasians. Significant differences in allele frequency for nearly all the genotyped single nucleotide polymorphism (SNPs) were detected between the two ethnic groups. Linkage disequilibrium (LD) analysis of this locus revealed two haplotype blocks characterized by strong LD and reduced haplotype diversity, especially in Caucasians. Between the two blocks is a narrow (approximately 3 kb) recombination hotspot centred on exons 4 and 5, and a widely used genetic marker in association studies in this region (rs7121) was in linkage equilibrium with the rest of the gene. The haplotype structure of the GNAS locus warrants reevaluation of previous association studies that used marker rs7121 and affects choice of SNP markers to be used in future studies of this locus.","PeriodicalId":19917,"journal":{"name":"Pharmacogenetics","volume":"14 11","pages":"741-7"},"PeriodicalIF":0.0,"publicationDate":"2004-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1097/00008571-200411000-00005","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"24832979","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}

引用次数: 14

The T341C (Ile114Thr) polymorphism of N-acetyltransferase 2 yields slow acetylator phenotype by enhanced protein degradation. n -乙酰转移酶2的T341C (Ile114Thr)多态性通过增强蛋白质降解产生缓慢的乙酰化表型。

Pharmacogenetics Pub Date : 2004-11-01 DOI: 10.1097/00008571-200411000-00002

Yu Zang, Shuang Zhao, Mark A Doll, J Christopher States, David W Hein

{"title":"The T341C (Ile114Thr) polymorphism of N-acetyltransferase 2 yields slow acetylator phenotype by enhanced protein degradation.","authors":"Yu Zang, Shuang Zhao, Mark A Doll, J Christopher States, David W Hein","doi":"10.1097/00008571-200411000-00002","DOIUrl":"https://doi.org/10.1097/00008571-200411000-00002","url":null,"abstract":"Objectives: Human N-acetyltransferase 2 (NAT2) plays a significant role in the clearance and biotransformation of many drugs and carcinogens. A TC (Ile114Thr) single nucleotide polymorphism (SNP) of NAT2 is commonly found in slow acetylators, leading to altered drug response and toxicity and possibly cancer susceptibility from carcinogens. The objective of this study was to investigate the mechanism by which this SNP causes slow acetylator phenotype.Methods: A cDNA expression system was used to compare the NAT2*4 reference allele with an identical one possessing the TC SNP in COS-1 cells. The recombinant human NAT2 enzymes were compared in regard to catalytic activity, kinetic parameters, thermostability, immunoreactive protein level, mRNA level and in-vivo protein degradation.Results: The TC (Ile114Thr) SNP significantly reduced enzyme activity without changing the apparent kinetic parameters Km and Vmax (normalized for NAT2 protein), indicating that Ile114Thr did not change substrate or cofactor binding affinities or catalytic efficiency. Furthermore, no significant difference in NAT2 mRNA level was observed, indicating no impairment of transcription. The TC (Ile114Thr) SNP did not alter thermostability of NAT2 at either 37 or 50 degrees C. However, this SNP significantly reduced cytosolic NAT2 immunoreactive protein through enhanced protein degradation.Conclusion: This is the first report indicating that protein degradation is an important mechanism of human NAT2 slow acetylator phenotype.","PeriodicalId":19917,"journal":{"name":"Pharmacogenetics","volume":"14 11","pages":"717-23"},"PeriodicalIF":0.0,"publicationDate":"2004-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1097/00008571-200411000-00002","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"24832976","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}

引用次数: 59

Association between single nucleotide polymorphisms in deoxycytidine kinase and treatment response among acute myeloid leukaemia patients. 急性髓性白血病患者脱氧胞苷激酶单核苷酸多态性与治疗反应的关系

Pharmacogenetics Pub Date : 2004-11-01 DOI: 10.1097/00008571-200411000-00007

Jing-Yi Shi, Zhan-Zhong Shi, Su-Jiang Zhang, Yong-Mei Zhu, Bai-Wei Gu, Guo Li, Xue-Tao Bai, Xiao-Dong Gao, Jiong Hu, Wei Jin, Wei Huang, Zhu Chen, Sai-Juan Chen

{"title":"Association between single nucleotide polymorphisms in deoxycytidine kinase and treatment response among acute myeloid leukaemia patients.","authors":"Jing-Yi Shi, Zhan-Zhong Shi, Su-Jiang Zhang, Yong-Mei Zhu, Bai-Wei Gu, Guo Li, Xue-Tao Bai, Xiao-Dong Gao, Jiong Hu, Wei Jin, Wei Huang, Zhu Chen, Sai-Juan Chen","doi":"10.1097/00008571-200411000-00007","DOIUrl":"https://doi.org/10.1097/00008571-200411000-00007","url":null,"abstract":"Development of resistance to 1-beta-arabinofuranosylcytosine (AraC) is a major obstacle in the treatment of patients with acute myeloid leukaemia (AML). Deficiency of functional deoxycytidine kinase (dCK) plays an important role in AraC resistance in vitro. We screened 5378 bp sequences of the dCK gene, including all exons and the 5' flanking region, and identified two single nucleotide polymorphisms (SNPs) in the regulatory region (rSNPs) with high allele frequencies. These two rSNPs (-201C>T and -360C>G) formed two major haplotypes. Genotyping with sequencing and MassARRAY system among 122 AML patients showed that those with -360CG/-201CT and -360GG/-201TT compound genotypes (n = 41) displayed a favourable response to chemotherapy whereas those with -360CC/-201CC (n = 81) tended to have a poor response (P = 0.025). Moreover, real-time quantitative reverse transcriptase-polymerase chain reaction showed that patients with -360CG/-201CT and -360GG/-201TT genotypes expressed higher level of dCK mRNA compared to those with the -360CC/-201CC genotype (P = 0.0034). Luciferase-reporter assay showed that dCK 5' regulatory region bearing -360G/-201T genotype alone had an eight-fold greater transcriptional activation activity compared to that with -360C/-201C genotype, whereas co-transfection of both -360G/-201T and -360C/-201C constructs mimicked the heterozygous genotype, which exhibited a four-fold greater activity compared to that with -360C/-201C. These results indicate that rSNP haplotypes of dCK gene may serve as a genetic marker for predicting drug responsiveness, which will be beneficial in establishing more effective AML chemotherapeutic regimens.","PeriodicalId":19917,"journal":{"name":"Pharmacogenetics","volume":"14 11","pages":"759-68"},"PeriodicalIF":0.0,"publicationDate":"2004-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1097/00008571-200411000-00007","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"24832981","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}

引用次数: 76

Benzydamine metabolism in vivo is impaired in patients with deficiency of flavin-containing monooxygenase 3. 含黄素单加氧酶3缺乏的患者体内苄胺代谢受损。

Pharmacogenetics Pub Date : 2004-11-01 DOI: 10.1097/00008571-200411000-00009

Ertan Mayatepek, Bianca Flock, Johannes Zschocke

引用次数: 29

Lack of association between the ITPA 94C>A polymorphism and adverse effects from azathioprine. ITPA 94C>A 多态性与硫唑嘌呤的不良反应之间缺乏关联。

Pharmacogenetics Pub Date : 2004-11-01 DOI: 10.1097/00008571-200411000-00010

Richard B Gearry, Rebecca L Roberts, Murray L Barclay, Martin A Kennedy

引用次数: 114

Identification of non-functional allelic variant of CYP1A2 in dogs. 犬CYP1A2无功能等位基因变异的鉴定。

Pharmacogenetics Pub Date : 2004-11-01 DOI: 10.1097/00008571-200411000-00008

Masashi Mise, Takanori Hashizume, Satoshi Matsumoto, Yoshiaki Terauchi, Toshihiko Fujii

{"title":"Identification of non-functional allelic variant of CYP1A2 in dogs.","authors":"Masashi Mise, Takanori Hashizume, Satoshi Matsumoto, Yoshiaki Terauchi, Toshihiko Fujii","doi":"10.1097/00008571-200411000-00008","DOIUrl":"https://doi.org/10.1097/00008571-200411000-00008","url":null,"abstract":"Objectives: Recently, we reported that AC-3933, a novel cognitive enhancer, is polymorphically hydroxylated in beagle dogs and that dogs could be phenotyped as extensive metabolizers (EM) or poor metabolizers (PM). AC-3933 polymorphic hydroxylation is caused by polymorphic expression of CYP1A2 protein in dog liver.Methods: In order to clarify the mechanism of polymorphic expression of CYP1A2 protein in beagle dogs, we investigated, in this study, the sequence of CYP1A2 cDNA in EM and PM dogs.Results: In PM dogs CYP1A2 gene, we discovered a nonsense mutation (C1117T) that induces a premature termination, and is associated with PM phenotype for AC-3933 hydroxylation. All PM dogs studied were homozygote of the mutant allele (m/m) and seemed to be CYP1A2-null phenotype as they lacked the heme-binding region in CYP1A2. These results indicate that the polymorphic expression of CYP1A2 protein observed in our previous study is caused by a single nucleotide polymorphism on CYP1A2 coding region. Furthermore, we developed a genotyping method for the mutant allele using a mismatch PCR-restriction fragment length polymorphism, and carried out frequency analysis in 149 beagle dogs.Conclusion: Our results indicate that more than 10% of the dogs studied were CYP1A2-null. Because CYP1A2-null phenotype in dogs affects the results of pharmacokinetic, toxicological and pharmacological studies of drug candidates, these findings are important in the pharmaceutical and the veterinary fields.","PeriodicalId":19917,"journal":{"name":"Pharmacogenetics","volume":"14 11","pages":"769-73"},"PeriodicalIF":0.0,"publicationDate":"2004-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1097/00008571-200411000-00008","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"24832870","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}

引用次数: 34

The Arg389Gly beta1-adrenoceptor gene polymorphism determines contractile response to catecholamines. Arg389Gly - β -肾上腺素受体基因多态性决定了对儿茶酚胺的收缩反应。

Pharmacogenetics Pub Date : 2004-11-01 DOI: 10.1097/00008571-200411000-00001

Karl La Rosée, Michael Huntgeburth, Stephan Rosenkranz, Michael Böhm, Petra Schnabel

{"title":"The Arg389Gly beta1-adrenoceptor gene polymorphism determines contractile response to catecholamines.","authors":"Karl La Rosée, Michael Huntgeburth, Stephan Rosenkranz, Michael Böhm, Petra Schnabel","doi":"10.1097/00008571-200411000-00001","DOIUrl":"https://doi.org/10.1097/00008571-200411000-00001","url":null,"abstract":"Objectives: Recently, the Arg389Gly beta1-adrenoceptor (beta1AR) gene polymorphism has been detected. The Arg variant exhibited increased responsiveness to agonist-induced stimulation in vitro. Functional studies in isolated human atrial muscle strips and in-vivo studies revealed contradictory results regarding the functional relevance of this polymorphism. We sought to characterize the functional consequences of the Arg389Gly beta1-AR polymorphism in 30 consecutive healthy male volunteers in vivo.Methods: beta1-AR genotype was determined by PCR and restriction analysis, which was confirmed by DNA sequencing. We compared heart rate, blood pressure, and contractile response of the various genotype carriers with a modified dobutamine stress echocardiography protocol.Results: Subjects homozygous for the Arg389 beta1AR showed a significantly higher increase in fractional shortening upon cumulative doses of dobutamine as compared to subjects carrying one or two copies of the Gly389 allele. A statistically significant difference was observed at a dobutamine dose of 10 microg/kg/min (46.5 +/- 1.3 vs. 41.8 +/- 1.0 %; P = 0.023) and was maximal at 40 microg/kg/min (61.9 +/- 1.4 vs. 52.8 +/- 1.6; P = 0.001). As a result, the systolic blood pressure response to dobutamine was significantly enhanced in individuals homozygous for the Arg389 allele, whereas the effect on heart rate did not differ between the two groups. Normalization for changing afterload conditions by calculating the pressure-dimension ratio revealed similar effects, indicating that the beta1AR-mediated effects are mainly a result of increased myocardial inotropy.Conclusion: These data indicate that the Arg389Gly beta1AR polymorphism is functionally relevant in vivo and determines contractile responsiveness to catecholamines in humans.","PeriodicalId":19917,"journal":{"name":"Pharmacogenetics","volume":"14 11","pages":"711-6"},"PeriodicalIF":0.0,"publicationDate":"2004-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1097/00008571-200411000-00001","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"24832975","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}

引用次数: 65

Functionality of allelic variations in human alcohol dehydrogenase gene family: assessment of a functional window for protection against alcoholism. 人类酒精脱氢酶基因家族等位基因变异的功能:对酒精中毒保护的功能窗口的评估

Pharmacogenetics Pub Date : 2004-11-01 DOI: 10.1097/00008571-200411000-00003

Shou-Lun Lee, Jan-Olov Höög, Shih-Jiun Yin

{"title":"Functionality of allelic variations in human alcohol dehydrogenase gene family: assessment of a functional window for protection against alcoholism.","authors":"Shou-Lun Lee, Jan-Olov Höög, Shih-Jiun Yin","doi":"10.1097/00008571-200411000-00003","DOIUrl":"https://doi.org/10.1097/00008571-200411000-00003","url":null,"abstract":"Alcohol dehydrogenase (ADH) catalyses the rate-determining reaction in ethanol metabolism. Genetic association studies of diverse ethnic groups have firmly demonstrated that the allelic variant ADH1B*2 significantly protects against alcoholism but that ADH1C*1, which is in linkage with ADH1B*2, produces a negligible protection. The influence of other potential candidate genes/alleles within the human ADH family, ADH1B*3 and ADH2, remains unclear or controversial. To address this question, functionalities of ADH1B3 and ADH2 were assessed at a physiological level of coenzyme and substrate range. Ethanol-oxidizing activities of recombinant ADH1B1, ADH1B2, ADH1B3, ADH1C1, ADH1C2 and ADH2 were determined at pH 7.5 in the presence of 0.5 mm NAD with 2-50 mm ethanol. The activity differences between ADH1B2 and ADH1B1 were taken as a threshold for effective protection against alcoholism and those between ADH1C1 and ADH1C2 as a threshold for null protection. Over 2-50 mm ethanol, the activities of ADH1B3 were found 2.9-23-fold lower than those of ADH1B2, largely attributed to the Km effect (ADH1B2, 1.8 mm; ADH1B3, 61 mm). Strikingly, the ADH1B3 activity was only 84% that of ADH1B1 at a low ethanol concentration, 2 mm, but increased 10-fold at 50 mm. Corrected for relative expression levels of the enzyme in liver, the hepatic ADH2 activities were estimated to be 18-97% those of ADH1B1 over 2-50 mm ethanol and were 28-140% of the activity differences between ADH1C1 and ADH1C2. The assessment based on the proposed functional window for the human ADH gene family indicates that ADH1B*3 may show some degree of protection against alcoholism and that the ADH2 functional variants appear to be negligible for this protection.","PeriodicalId":19917,"journal":{"name":"Pharmacogenetics","volume":"14 11","pages":"725-32"},"PeriodicalIF":0.0,"publicationDate":"2004-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1097/00008571-200411000-00003","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"24832977","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}

引用次数: 50