992 results match your criteria Pharmacogenetics[Journal]


No evidence of a role for PPARgamma Pro12Ala polymorphism in endometrial cancer susceptibility.

Pharmacogenetics 2004 Dec;14(12):851-6

Department of Epidemiology, Harvard School of Public Health, Boston, MA, USA.

Endogenous oestrogens play a crucial role in endometrial cancer pathogenesis, with most endometrial cancer risk factors causing an increase in oestrogens. Adipose tissue, where androgens are converted to oestrogens by the enzyme aromatase, is an important source of endogenous oestrogen production in the postmenopausal woman. The peroxisome proliferator-activated receptor-gamma (PPARgamma), a key transcriptional regulator of adipogenesis, may also play a role in the regulation of aromatase expression in adipose tissue. Read More

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December 2004
2 Reads

Pharmacogenetics and herb-drug interactions: experience with Ginkgo biloba and omeprazole.

Pharmacogenetics 2004 Dec;14(12):841-50

School of Pharmacy, the Chinese University of Hong Kong, Shatin, New Territories, Hong Kong.

Objective: Ginkgo biloba was found to exert a significant inductive effect on CYP2C19 activity. This study was designed to investigate the potential herb-drug interaction between G. biloba and omeprazole, a widely used CYP2C19 substrate, in subjects with different CYP2C19 genotypes. Read More

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December 2004
24 Reads

Functional comparison of the endothelial nitric oxide synthase Glu298Asp polymorphic variants in human endothelial cells.

Pharmacogenetics 2004 Dec;14(12):831-9

Department of Cardiovascular Medicine, University of Oxford, John Radcliffe Hospital, Oxford, UK.

The G894T endothelial nitric oxide synthase (eNOS) polymorphism results in a Glu to Asp substitution at position 298. This position is located externally on the protein and as the regulation of eNOS is dependent on its subcellular localization and interaction with modulatory proteins, we aimed to address whether the substitution of Asp at 298 had any effect on these mechanisms. Initially, we developed a novel method to accurately determine molar quantities of each variant by expressing them as green fluorescent protein (GFP) fusion proteins and using recombinant adenoviruses to facilitate transient infection of human microvascular endothelial cells. Read More

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December 2004
5 Reads

Response to micronized fenofibrate treatment is associated with the peroxisome-proliferator-activated receptors alpha G/C intron7 polymorphism in subjects with type 2 diabetes.

Pharmacogenetics 2004 Dec;14(12):823-9

Laboratoires Fournier S.A. Centre de Recherches, Department of Clinical Research and Medical Affairs, Daix, France.

Objective: The association between polymorphisms in candidate genes related to lipoprotein metabolism and the reduction in plasma triglyceride (TG) in response to fenofibrate treatment was evaluated in subjects with type 2 diabetes treated with micronized fenofibrate (200 mg/day) for at least 3 years in the Diabetes Atherosclerosis Intervention Study.

Methods: The cholesteryl ester transfer protein Taq1B, LPL S447X, hepatic lipase -514 C-->T, peroxisome-proliferator-activated receptors alpha (PPARA) L162V and G/C intron 7 polymorphisms and the apolipoprotein E2/E3/E4 alleles were genotyped using PCR and restriction enzyme digestion. Subjects were divided into high TG-responders (with > 30% TG relative reduction after treatment) and low TG-responders. Read More

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December 2004
2 Reads

Upstream and coding region CYP2C9 polymorphisms: correlation with warfarin dose and metabolism.

Pharmacogenetics 2004 Dec;14(12):813-22

School of Clinical and Laboratory Sciences, University of Newcastle upon Tyne, Medical School, Newcastle upon Tyne, UK.

Objectives: To assess whether CYP2C9 alleles other than CYP2C9*2 and *3 are associated with a low-warfarin dose requirement and the relevance of upstream CYP2C9 polymorphisms to dose requirement and metabolism.

Methods: CYP2C9 exons, intron-exon boundaries and 3 kb of upstream sequence in 20 patients requiring Read More

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December 2004
2 Reads

The human serotonin receptor 2B: coding region polymorphisms and association with vulnerability to illegal drug abuse.

Pharmacogenetics 2004 Dec;14(12):805-11

Molecular Neurobiology Branch, NIH/NIDA-IRP, 5500 Nathan Shock Dr., Baltimore, MD 21224, USA.

Objective And Methods: 5-Hydroxytryptamine (serotonin) receptor 2B (HTR2B) is involved in brain development. Although expressed in the human brain, HTR2B has not been investigated much for its role in higher brain functions. Here we describe a genome-scan with 391 simple sequence repeat markers in 300 Caucasians, identifying HTR2B gene as a candidate for drug abuse vulnerability. Read More

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December 2004
2 Reads

Redefinition of the human kappa opioid receptor gene (OPRK1) structure and association of haplotypes with opiate addiction.

Pharmacogenetics 2004 Dec;14(12):793-804

aLaboratory of the Biology of Addictive Diseases, The Rockefeller University, New York, NY 10021, USA.

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. Read More

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December 2004
6 Reads
30 Citations

Methylenetetrahydrofolate reductase gene polymorphisms and response to fluorouracil-based treatment in advanced colorectal cancer patients.

Pharmacogenetics 2004 Dec;14(12):785-92

Centre Antoine Lacassagne, Nice, France.

Methylenetetrahydrofolate reductase (MTHFR) controls intracellular CH2FH4 concentrations (required for optimal fluoropyrimidine efficacy) by irreversibly converting CH2FH4 into 5-methyltetrahydrofolate. MTHFR 677C>T and 1298A>C polymorphisms are linked to altered enzyme activity. Thus, mutated MTHFR tumours should, in theory, be more sensitive to 5-fluorouracil (5FU) than wild-type tumours. Read More

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December 2004
5 Reads

HLA-B*5701 and abacavir hypersensitivity.

Pharmacogenetics 2004 Nov;14(11):783-4; author reply 784

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November 2004
2 Reads

Lack of association between the ITPA 94C>A polymorphism and adverse effects from azathioprine.

Pharmacogenetics 2004 Nov;14(11):779-81

Department of Medicine, Christchurch School of Medicine and Health Sciences, Christchurch, New Zealand.

A 94C>A missense mutation in the ITPA gene which encodes inosine triphosphate pyrophosphatase has been associated with adverse effects from azathioprine, specifically flu-like symptoms, pancreatitis and rash. We hypothesized that this association may also be present in a larger, population-based group of inflammatory bowel disease patients intolerant of thiopurine drugs. We performed genotyping for this polymorphism and TPMT*2 and TPMT*3 in 73 such patients and 74 patients with inflammatory bowel disease who have tolerated azathioprine. Read More

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November 2004
2 Reads

Benzydamine metabolism in vivo is impaired in patients with deficiency of flavin-containing monooxygenase 3.

Pharmacogenetics 2004 Nov;14(11):775-7

Department of General Pediatrics, University Children's Hospital, Düsseldorf, Germany.

Flavin-containing monooxygenase 3 (FMO3) is an important hepatic enzyme for the detoxification of xenobiotics. The pharmacogenetic relevance of FMO3 deficiency has frequently been postulated from in vitro studies but has not yet been proven in vivo. We investigated the metabolism of benzydamine (BZD) in controls as well as patients with severe FMO3 deficiency and found evidence of markedly reduced N-oxygenation capacity both in serum and urine samples. Read More

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November 2004
6 Reads

Identification of non-functional allelic variant of CYP1A2 in dogs.

Pharmacogenetics 2004 Nov;14(11):769-73

Pharmacokinetics and Physico-Chemical Property Research Laboratories, Dainippon Pharmaceutical Co., Ltd., Osaka, Japan.

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. Read More

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November 2004
3 Reads

Association between single nucleotide polymorphisms in deoxycytidine kinase and treatment response among acute myeloid leukaemia patients.

Pharmacogenetics 2004 Nov;14(11):759-68

State Key Laboratory of Medical Genomics Shanghai Institute of Hematology, Shanghai, PR China.

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. Read More

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November 2004
5 Reads

Functional analysis of single nucleotide polymorphisms of hepatic organic anion transporter OATP1B1 (OATP-C).

Pharmacogenetics 2004 Nov;14(11):749-57

Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan.

Objective: 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. Read More

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November 2004
2 Reads

Complex haplotype structure of the human GNAS gene identifies a recombination hotspot centred on a single nucleotide polymorphism widely used in association studies.

Pharmacogenetics 2004 Nov;14(11):741-7

Department of Cell and Molecular Pharmacology, Medical University of South Carolina, Charleston, South Carolina, USA.

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. Read More

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November 2004
1 Read

Contribution of common polymorphisms in reduced folate carrier and gamma-glutamylhydrolase to methotrexate polyglutamate levels in patients with rheumatoid arthritis.

Pharmacogenetics 2004 Nov;14(11):733-9

Prometheus Laboratories, San Diego, California, USA.

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. Read More

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November 2004
4 Reads

Functionality of allelic variations in human alcohol dehydrogenase gene family: assessment of a functional window for protection against alcoholism.

Pharmacogenetics 2004 Nov;14(11):725-32

Department of Biochemistry, National Defense Medical Center, Taipei, Taiwan.

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. Read More

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November 2004
1 Read

The T341C (Ile114Thr) polymorphism of N-acetyltransferase 2 yields slow acetylator phenotype by enhanced protein degradation.

Pharmacogenetics 2004 Nov;14(11):717-23

Department of Pharmacology and Toxicology and James Graham Brown Cancer Center, and Center for Genetics and Molecular Medicine, University of Louisville School of Medicine, Louisville, KY, USA.

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. Read More

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November 2004
5 Reads

The Arg389Gly beta1-adrenoceptor gene polymorphism determines contractile response to catecholamines.

Pharmacogenetics 2004 Nov;14(11):711-6

Klinik III für Innere Medizin, Universität zu Köln, Germany.

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. Read More

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November 2004
3 Reads

A coding polymorphism in the CYSLT2 receptor with reduced affinity to LTD4 is associated with asthma.

Pharmacogenetics 2004 Sep;14(9):627-33

Genetics Research, GlaxoSmithKline Research Triangle Park, NC, USA.

Background: Cysteinyl leukotrienes (CYSLTR) are potent biological mediators in the pathophysiology of asthma for which two receptors have been characterized, CYSLTR1 and CYSLTR2. The leukotriene modifying agents currently used to control bronchoconstriction and inflammation in asthmatic patients are CYSLTR1-specific leukotriene receptor antagonists. In this report, we investigated a possible role for therapeutic modulation of CYSLTR2 in asthma by investigating genetic association with asthma and further characterization of the pharmacology of a coding polymorphism. Read More

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September 2004
11 Reads

Ethnic variation in CYP2A6 and association of genetically slow nicotine metabolism and smoking in adult Caucasians.

Pharmacogenetics 2004 Sep;14(9):615-26

Department of Pharmacology, University of Toronto, Toronto, Ontario, Canada.

Genetically variable CYP2A6 is the primary enzyme that inactivates nicotine to cotinine. Our objective was to investigate allele frequencies among five ethnic groups and to investigate the relationship between genetically slow nicotine metabolic inactivation and smoking status, cigarette consumption, age of first smoking and duration of smoking. Chinese, Japanese, Canadian Native Indian, African-North American and Caucasian DNA samples were assessed for CYP2A6 allelic frequencies (CYP2A6*1B-*12,*1x2). Read More

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September 2004
5 Reads

Pharmacogenetics of selective serotonin reuptake inhibitor response: a 6-month follow-up.

Pharmacogenetics 2004 Sep;14(9):607-13

Department of Psychiatry, Vita-Salute University, San Raffaele Hospital, Milan, Italy.

Background: We previously reported the association between some genetic factors and short-term antidepressant outcome. In the present paper we investigated the same gene variants in a prospective 6-months naturalistic follow-up.

Methods: The sample included 185 inpatients affected by recurrent major depression consecutively admitted to the Psychiatric Inpatient Unit of San Raffaele Hospital from 1998 to 2003 and prospectively followed for 6 months after their recovery. Read More

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September 2004
3 Reads

Determination and analysis of single nucleotide polymorphisms and haplotype structure of the human carboxylesterase 2 gene.

Pharmacogenetics 2004 Sep;14(9):595-605

Department of Medicine, University of Chicago, Chicago, Illinois, USA.

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). Read More

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September 2004
5 Reads

The effect of rare human sequence variants on the function of vesicular monoamine transporter 2.

Pharmacogenetics 2004 Sep;14(9):587-94

Department of Neurology, UCSF School of Medicine, San Francisco, CA 94143-2140, USA.

The extent to which genetic variation in a population contributes to phenotypic variation depends on the frequency of sequence polymorphisms and the effect of these polymorphisms on function. The frequency of polymorphisms might also reflect the severity of their effects on function. We therefore examined the effect of very rare single nucleotide polymorphisms (SNPs) on the activity of the vesicular monoamine transporter 2 (VMAT2, SLC18A2), a gene implicated in neuropsychiatric disease. Read More

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September 2004
7 Reads

Extracting and characterizing gene-drug relationships from the literature.

Pharmacogenetics 2004 Sep;14(9):577-86

Department of Genetics, Stanford Biomedical Informatics, Stanford, CA 94305-5120, USA.

A fundamental task of pharmacogenetics is to collect and classify relationships between genes and drugs. Currently, this useful information has not been comprehensively aggregated in any database and remains scattered throughout the published literature. Although there are efforts to collect this information manually, they are limited by the size of the published literature on gene-drug relationships. Read More

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September 2004
1 Read

Maternal/newborn GSTT1 null genotype contributes to risk of preterm, low birthweight infants.

Pharmacogenetics 2004 Sep;14(9):569-76

Department of Medicine, The Center of Clinical Pharmacology, Pittsburgh, PA, USA.

Objectives: Maternal cigarette smoke exposure during pregnancy has been identified as a risk factor for prematurity and low birthweight. However, little is known about genetic susceptibility and possible interactions with cigarette smoking which may increase risk of these events.

Methods: Maternal peripheral and umbilical cord blood samples from 955 mother/newborn pairs were genotyped for a panel of phase I/II metabolic enzymes responsible for the metabolism of tobacco related mutagens and carcinogens in order to evaluate the association with premature birth. Read More

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September 2004
3 Reads

Identification of deletion-junction site of CYP2A6*4B allele lacking entire coding region of CYP2A6 in Japanese.

Pharmacogenetics 2004 Oct;14(10):701-5

Laboratory of Drug Metabolism, Division of Pharmacobio-dynamics, Graduate School of Pharmaceutical Sciences, Hokkaido University, Sapporo, Japan.

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October 2004
2 Reads

Increased levels of aflatoxin-albumin adducts are associated with CYP3A5 polymorphisms in The Gambia, West Africa.

Pharmacogenetics 2004 Oct;14(10):691-700

Department of Pharmacology, University Mainz, Obere Zahlbacher Str. 67, D-55101 Mainz, Germany.

Objectives: 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. Read More

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October 2004
3 Reads

Association between a polymorphism in cysteinyl leukotriene receptor 2 on chromosome 13q14 and atopic asthma.

Pharmacogenetics 2004 Oct;14(10):683-90

Department of Medical Genetics, Graduate School of Comprehensive Human Sciences, University of Tsukuba, Tsukuba, 305-8575, Japan.

Objective: 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. Read More

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October 2004
5 Reads

Angiotensin II type I receptor gene and myocardial infarction: tagging SNPs and haplotype based association study. The Beijing atherosclerosis study.

Pharmacogenetics 2004 Oct;14(10):673-81

The Division of Population Genetics and Prevention, Fu Wai Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, 167 Beilishi Road, Beijing 100037, China.

Objectives: The present study aimed to assess the effect of haplotype variation in angiotensin II type I receptor (AGTR1) gene on the risk of myocardial infarction (MI) in Chinese males.

Methods: We used 48 patients to identify the putative functional polymorphisms in AGTR1 gene by direct sequencing. The program tagSNPs was used to identify an optimal set of tagging single nucleotide polymorphisms (SNPs). Read More

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October 2004
6 Reads

The effect of variable CYP3A5 expression on cyclosporine dosing, blood pressure and long-term graft survival in renal transplant patients.

Pharmacogenetics 2004 Oct;14(10):665-71

Abteilung Klinische Pharmakologie, Charité - Universitätsmedizin Berlin, Campus Benjamin Franklin, Hindenburgdamm 30, 12200 Berlin, Germany.

Objective: 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. Read More

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October 2004
1 Read

Functional polymorphism of human glutathione transferase A3: effects on xenobiotic metabolism and steroid biosynthesis.

Pharmacogenetics 2004 Oct;14(10):657-63

Molecular Genetics Group, Division of Molecular Bioscience, John Curtin School of Medical Research, Australian National University, Canberra, Australia.

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. Read More

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October 2004
1 Read

Identification and characterization of the FMO2 gene in Rattus norvegicus: a good model to study metabolic and toxicological consequences of the FMO2 polymorphism.

Pharmacogenetics 2004 Oct;14(10):647-55

Unite 1233 INRA/ENVL Metabolisme et toxicologie compares des xenobiotiques, National Veterinary School of Lyon, BP 83, 69280 Marcy l'Etoile, France.

Background: 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. Read More

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October 2004
9 Reads

Regulation of CYP3A4 by the bile acid receptor FXR: evidence for functional binding sites in the CYP3A4 gene.

Pharmacogenetics 2004 Oct;14(10):635-45

Division of Pharmacology and Neurobiology, Biozentrum of the University of Basel, Klingelbergstrasse 50-70, CH-4056 Basel, Switzerland.

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. Read More

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October 2004
1 Read

A substrate specific functional polymorphism of human gamma-glutamyl hydrolase alters catalytic activity and methotrexate polyglutamate accumulation in acute lymphoblastic leukaemia cells.

Pharmacogenetics 2004 Aug;14(8):557-67

Department of Pharmaceutical Sciences, Hematological Malignancies Program, St Jude Children's Research Hospital, Memphis, Tennessee, USA.

We found a significant inverse relationship between gamma-glutamyl hydrolase (GGH) activity and the accumulation of long-chain methotrexate polyglutamates (MTXPG4-7) in non-hyperdiploid B-lineage acute lymphoblastic leukaemia (ALL) cells after uniform treatment with high-dose methotrexate (HDMTX) (1 g/m i.v.). Read More

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August 2004
3 Reads

Pharmacogenetic roles of CYP2C19 and CYP2B6 in the metabolism of R- and S-mephobarbital in humans.

Pharmacogenetics 2004 Aug;14(8):549-56

Laboratory of Pharmacology and Toxicology, Graduate School of Pharmaceutical Sciences, Chiba University, Chiba, Japan.

Objectives And Methods: We assessed the relationship between the metabolism of R- and S-mephobarbital (MPB) and genetic polymorphisms of cytochrome P450 (CYP) 2C19 and CYP2B6. Nine homozygous extensive metabolizers (homo-EMs, 2C19*1/2C19*1) of CYP2C19, ten heterozygous EMs (hetero-EMs, 2C19*1/2C19*2, 2C19*1/2C19*3) and eleven poor metabolizers (PMs, 2C19*2/2C19*2, 2C19*3/2C19*3, 2C19*2/2C19*3) recruited from a Japanese population, received an oral 200 mg-dose of racemic MPB. Blood and urine samples were collected, and R-MPB, S-MPB and the metabolites, phenobarbital (PB) and 4'-hydroxy-MPB, were measured. Read More

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August 2004
3 Reads

Relative impact of covariates in prescribing warfarin according to CYP2C9 genotype.

Pharmacogenetics 2004 Aug;14(8):539-47

Department of Care Management, Marshfield Clinic, Marshfield, Wisconsin, USA.

Patients on warfarin anticoagulant therapy demonstrate wide variation in maintenance dose. Patients possessing variants (*2 and *3) of the cytochrome P450 2C9 gene require reduced maintenance doses compared to those having wild-type alleles (*1). Many other clinical factors have been shown to affect warfarin dose as well. Read More

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August 2004
1 Read
39 Citations

Discovery of new potentially defective alleles of human CYP2C9.

Pharmacogenetics 2004 Aug;14(8):527-37

Laboratory of Pharmacology and Chemistry, Human Metabolism Section, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina, USA, DNA.

CYP2C9 is a clinically important enzyme, responsible for the metabolism of numerous clinically important therapeutic drugs. In the present study, we discovered 38 single nucleotide polymorphisms in CYP2C9 by resequencing of genomic DNA from 92 individuals from three different racial groups. Haplotype analysis predicted that there are at least 21 alleles of CYP2C9 in this group of individuals. Read More

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August 2004
5 Reads

Lipid-lowering response to statins is affected by CYP3A5 polymorphism.

Pharmacogenetics 2004 Aug;14(8):523-5

Dr Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, Germany.

Individuals expressing the polymorphic CYP3A5 enzyme might show a more than average efficiency in the metabolism of lovastatin, simvastatin and atorvastatin. We studied whether the expression of CYP3A5 is associated with an impaired lipid-lowering response to statins in 69 Caucasian patients. Lovastatin, simvastatin and atorvastatin were significantly less effective in CYP3A5 expressors than in non-expressors. Read More

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August 2004
1 Read

Beta2-adrenoceptor Thr164Ile polymorphism is associated with markedly decreased vasodilator and increased vasoconstrictor sensitivity in vivo.

Pharmacogenetics 2004 Aug;14(8):517-22

Division of Clinical Pharmacology and General Clinical Research Center Division of General Internal Medicine, Department of Medicine and the Department of Biostatistics, Vanderbilt University Medical Center, Nashville TN, USA.

Background: The uncommon Thr164Ile polymorphism of the beta2-adrenoceptor is associated with profoundly altered responses to agonist in vitro; however its effects on vascular responses in vivo are not known. Altered adrenergic vascular sensitivity may contribute to the decreased survival observed in patients with congestive heart failure carrying the Ile164 allele.

Methods And Results: We used the linear variable differential transformer dorsal hand vein technique to compare vasodilation in response to the beta-adrenergic receptor agonist, isoproterenol, and vasoconstriction in response to the alpha-adrenergic receptor agonist, phenylephrine, in healthy homozygous (Thr164/Thr164) (n = 21) and heterozygous Thr164/Ile164 (n = 5) women. Read More

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August 2004
9 Reads

Identification of common polymorphisms in the promoter of the UGT1A9 gene: evidence that UGT1A9 protein and activity levels are strongly genetically controlled in the liver.

Pharmacogenetics 2004 Aug;14(8):501-15

Canada Research Chair in Pharmacogenomics, Laboratory of Pharmacogenomics, Oncology and Molecular Endocrinology Research Center, CHUL Research Center and Faculty of Pharmacy, Laval University, Québec, Canada.

Objectives: Polymorphisms in UDP-glucuronosyltransferases (UGTs) can influence detoxifying capacities and have considerable therapeutic implications in addition to influence various (patho)physiological processes. UGT1A9 plays a central role in the metabolism of various classes of therapeutic drugs in addition to carcinogens and steroids. The great interindividual variability of UGT1A9-mediated glucuronidation remains poorly explained, while evidence for its genetic origin exists. Read More

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August 2004
10 Reads

Human UGT1A6 pharmacogenetics: identification of a novel SNP, characterization of allele frequencies and functional analysis of recombinant allozymes in human liver tissue and in cultured cells.

Pharmacogenetics 2004 Aug;14(8):487-99

Department of Pharmacology, Fox Chase Cancer Center, Philadelphia, PA, USA.

Background: UDP-glucuronosyltransferase (UGT) enzymes catalyze the glucuronidation and typically inactivation of endogenous and exogenous molecules including steroid hormones, bilirubin and many drugs. The UGT1A6 protein is expressed predominantly in liver and metabolizes small phenolic drugs including acetaminophen, salicylates and many beta-blockers. Interindividual variation in the capacity of humans to glucuronidate drugs has been observed. Read More

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August 2004
1 Read

Association of paraoxonase-1 M55L genotype and alcohol consumption with coronary atherosclerosis: the Helsinki Sudden Death Study.

Pharmacogenetics 2004 Aug;14(8):479-85

Laboratory of Atherosclerosis Genetics, Tampere University Hospital, Centre for Laboratory Medicine and Department of Clinical Chemistry, University of Tampere, Medical School, Tampere, Finland.

High-density lipoprotein (HDL) level is inversely correlated with coronary heart disease risk. Paraoxonase-1 (PON1) is an HDL-associated anti-atherogenic enzyme. The activity of PON1 is affected by the methionine for leucine substitution at position 55 (M55L) and increased during regular moderate alcohol consumption, consistent with increased HDL cholesterol concentration. Read More

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August 2004
1 Read

Modulation of multidrug resistance P-glycoprotein 1 (ABCB1) expression in human heart by hereditary polymorphisms.

Pharmacogenetics 2004 Jun;14(6):381-5

Peter Holtz Research Center of Pharmacology and Experimental Therapeutics, Ernst-Moritz-Arndt-University Greifswald, Germany.

Objectives: 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. Read More

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June 2004
25 Reads

Polymorphic NF-Y dependent regulation of human nicotine C-oxidase (CYP2A6).

Pharmacogenetics 2004 Jun;14(6):369-79

Institute of Environmental Medicine, Division of Molecular Toxicology, Karolinska Institutet, 17177 Stockholm, Sweden.

Objectives: 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. Read More

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June 2004
4 Reads

Polymorphism of human mu class glutathione transferases.

Pharmacogenetics 2004 Jun;14(6):359-68

Molecular Genetics Group, Division of Molecular Bioscience, John Curtin School of Medical Research, Australian National University, Canberra ACT 2601, Australia.

Objectives And Methods: 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).

Results: Two new polymorphisms were detected and characterized in the GSTM3 gene. Read More

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June 2004
1 Read

Functional polymorphisms of UDP-glucuronosyltransferases 1A1, 1A6 and 1A8 are not involved in chronic pancreatitis.

Pharmacogenetics 2004 Jun;14(6):351-7

Department of Medicine, Division of Gastroenterology and Hepatology, University Medical Centre St Radboud, Nijmegen, The Netherlands.

Objectives: Chronic pancreatitis (CP) is associated with alcohol abuse, smoking and other dietary or environmental factors. UDP-glucuronosyltransferases (UGTs) are phase II detoxifying enzymes responsible for glucuronidation of various exogenous and endogenous compounds. Genetic variations, resulting in variable rates of glucuronidation, are of toxicological and physiological importance and are frequently associated with diseases. Read More

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June 2004
24 Reads

Functional responses of human beta1 adrenoceptors with defined haplotypes for the common 389R>G and 49S>G polymorphisms.

Pharmacogenetics 2004 Jun;14(6):343-9

Clinical Pharmacology Unit, Level 6, Addenbrooke's Centre for Clinical Investigation, Addenbrooke's Hospital, Cambridge, CM6 2EE, UK.

Objectives: The human beta1-adrenoceptor (beta1-AR) is an important therapeutic target for cardiovascular diseases and has two common functional polymorphisms (49S>G and 389R>G). These polymorphisms have only been studied in isolation, however, and not in the context of the four haplotypes (SR, SG, GR and GG) that exist in native beta1-ARs.

Methods: To address this, the function of each of the receptor haplotypes was studied in HEK 293 cells stably transfected with appropriately modified human beta1-adrenoceptor cDNA sequence. Read More

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June 2004
2 Reads