Abstract:
:Two recent screens for copy-number variations in the entire human genome found 12.4 gene copy number variations per person, including 2.5% of individuals with gains between 7q21.1 and 7q22.1, the chromosomal location of CYP3A4. CYP3A4 is involved in the metabolism of approximately 50% of all drugs, including many cancer chemotherapeutic agents. CYP3A4 gene copy was determined in DNA from 143 individuals: normal human livers, primary and secondary liver tumors, human hepatic cell lines, and immortalized cell lines representing eight ethnically diverse populations. CYP3A4 gene copy was normal in all but one sample, a primary human hepatocellular carcinoma cell line (TONG/HCC). Southern blots of TONG/HCC DNA revealed an approximate 10-fold increase in CYP3A and a corresponding increase in CYP3A mRNA expression and catalytic activity. Fluorescent in situ hybridization of TONG/HCC revealed specific amplification of the CYP3A4 gene on chromosome 7q21 but no amplification of the MDR1 gene that localizes 11.9 Mb upstream of CYP3A4. High resolution analysis of DNA copy number by comparative genomic hybridization confirmed amplification at 7q21.3-7q22. The amplicon spanned 1.7 Mb and contained 30 known genes, including the entire CYP3A locus. To determine whether CYP3A4 expression affected chemotherapeutic toxicity, LLC-PK1 cells were transduced with adenoviruses expressing CYP3A4 and P450 reductase. CYP3A4 conferred resistance to taxol, vinblastine and topotecan. These studies demonstrate that CYP3A4 copy number differences do not contribute to the normal variation in CYP3A4 expression. Tumors with increased CYP3A copy number (via amplification or increased chromosome 7q) would be expected to show reduced cytotoxicity to some chemotherapeutic drugs and potentially an increase in the outgrowth of drug resistant tumors.
journal_name
Pharmacogenet Genomicsjournal_title
Pharmacogenetics and genomicsauthors
Lamba JK,Chen X,Lan LB,Kim JW,Wei Wang X,Relling MV,Kazuto Y,Watkins PB,Strom S,Sun D,Schuetz JD,Schuetz EGdoi
10.1097/01.fpc.0000194421.35641.70subject
Has Abstractpub_date
2006-06-01 00:00:00pages
415-27issue
6eissn
1744-6872issn
1744-6880pii
01213011-200606000-00004journal_volume
16pub_type
杂志文章abstract::The study aimed to investigate whether polymorphisms in genes of the EGFR signaling pathway are associated with clinical outcome in advanced colorectal cancer (CRC) patients treated with single-agent Cetuximab. Polymorphisms of interest in the EGFR pathway include: cyclin D1 (CCND1) A870G, cyclooxygenase 2 (Cox-2) G-7...
journal_title:Pharmacogenetics and genomics
pub_type: 临床试验,杂志文章,多中心研究
doi:10.1097/01.fpc.0000220562.67595.a5
更新日期:2006-07-01 00:00:00
abstract:OBJECTIVE:Corticotropin-releasing hormone receptor (CRHR)-2 participates in smooth muscle relaxation response and may influence acute airway bronchodilator response to short-acting beta2-agonist treatment of asthma. We aim to assess associations between genetic variants of CRHR2 and acute bronchodilator response in ast...
journal_title:Pharmacogenetics and genomics
pub_type: 杂志文章,多中心研究,随机对照试验
doi:10.1097/FPC.0b013e3282fa760a
更新日期:2008-05-01 00:00:00
abstract:OBJECTIVE:The effects of CYP2C9*1/*3 and *3/*3 genotypes on the pharmacokinetics and pharmacodynamics of meloxicam were evaluated in healthy Korean subjects. METHODS:After oral administration of 15 mg meloxicam, the plasma concentrations of meloxicam were assessed in 11 CYP2C9*1/*1 individuals, eight CYP2C9*1/*3 indiv...
journal_title:Pharmacogenetics and genomics
pub_type: 杂志文章
doi:10.1097/FPC.0000000000000025
更新日期:2014-02-01 00:00:00
abstract:OBJECTIVES:The methyltransferase genotype and pregnancy both influence the arsenic metabolism phenotype, but it is unknown whether these factors interact, explaining the drastic changes in the efficiency of arsenic metabolism observed among pregnant women. The aim of this study was to evaluate the relative contribution...
journal_title:Pharmacogenetics and genomics
pub_type: 杂志文章
doi:10.1097/FPC.0b013e3283535d6a
更新日期:2012-07-01 00:00:00
abstract:OBJECTIVE:To determine whether polymorphisms in the sulfonamide detoxification genes, CYB5A (encoding cytochrome b(5)), CYB5R3 (encoding cytochrome b(5) reductase), or NAT2 (encoding N-acetyltransferase 2) were over-represented in patients with delayed sulfonamide drug hypersensitivity, compared with control patients w...
journal_title:Pharmacogenetics and genomics
pub_type: 杂志文章
doi:10.1097/FPC.0b013e328357a735
更新日期:2012-10-01 00:00:00
abstract:OBJECTIVES:Flavin-containing monooxygenase 3 (FMO3) is involved in the metabolism of foreign chemicals, including therapeutic drugs, and thus mediates interactions between humans and their chemical environment. Loss-of-function mutations in the gene cause the inherited disorder trimethylaminuria, or fish-odour syndrome...
journal_title:Pharmacogenetics and genomics
pub_type: 杂志文章
doi:10.1097/FPC.0b013e328256b198
更新日期:2007-10-01 00:00:00
abstract:BACKGROUND:P-glycoprotein (P-gp) is a multidrug efflux transporter that has a defined role in the absorption and disposition of drugs. Many studies have investigated the potential influence of ABCB1 polymorphisms on the disposition of its substrates. However, there remains significant controversy regarding the role of ...
journal_title:Pharmacogenetics and genomics
pub_type: 杂志文章
doi:10.1097/FPC.0b013e328360d10c
更新日期:2013-06-01 00:00:00
abstract:OBJECTIVE:Exemestane is a third-generation aromatase inhibitor used in the treatment of breast cancer in postmenopausal women. Reduction to form 17-dihydroexemestane and subsequent glucuronidation to exemestane-17-O-glucuronide is a major pathway for exemestane metabolism. The goal of this study was to analyze 17-dihyd...
journal_title:Pharmacogenetics and genomics
pub_type: 杂志文章
doi:10.1097/FPC.0b013e32833b04af
更新日期:2010-10-01 00:00:00
abstract:OBJECTIVE:To investigate the effect of the Taq1A variant in the Dopamine D2 receptor gene (DRD2) and common functional genetic variants in the cytochrome P450 2D6 gene (CYP2D6) on prolactin levels in risperidone-treated boys with autism spectrum disorders and disruptive behavior disorders. METHODS:Forty-seven physical...
journal_title:Pharmacogenetics and genomics
pub_type: 杂志文章
doi:10.1097/FPC.0b013e3283647c33
更新日期:2013-09-01 00:00:00
abstract::Asthma is the leading chronic disease in children. Several studies have identified genetic biomarkers associated with susceptibility and severity in both adult and pediatric cases. In this study, we evaluated outcomes in 400 African American and European American pediatric cases all of whom were regular users of inhal...
journal_title:Pharmacogenetics and genomics
pub_type: 杂志文章
doi:10.1097/FPC.0000000000000355
更新日期:2018-11-01 00:00:00
abstract:OBJECTIVE:The immunosuppressive drug tacrolimus requires strict therapeutic monitoring due to its narrow therapeutic index and great inter-individual variability. Cytochrome P450 3A4 (Cyp3A4) and Cyp3A5 are the most important contributors to tacrolimus metabolism while the P-glycoprotein pump (MDR-1) modulates its bioa...
journal_title:Pharmacogenetics and genomics
pub_type: 杂志文章
doi:10.1097/01.fpc.0000220571.20961.dd
更新日期:2006-09-01 00:00:00
abstract:BACKGROUND/OBJECTIVES:The polymorphic hepatic enzyme CYP2C19 catalyzes the metabolism of clinically important drugs such as clopidogrel, proton-pump inhibitors, and others and clinical pharmacogenetic testing for clopidogrel is increasingly common. The CYP2C19*10 single-nucleotide polymorphism (SNP) is located 1 bp ups...
journal_title:Pharmacogenetics and genomics
pub_type: 杂志文章
doi:10.1097/FPC.0000000000000068
更新日期:2014-08-01 00:00:00
abstract:BACKGROUND:HIV infection has been associated with dyslipidemia, insulin resistance, and changes in body composition, including loss of subcutaneous fat and skeletal muscle, with relative sparing of upper trunk and visceral fat. Because of its resemblance to Cushing's syndrome, caused by glucocorticoid excess, we hypoth...
journal_title:Pharmacogenetics and genomics
pub_type: 杂志文章
doi:10.1097/FPC.0000000000000029
更新日期:2014-03-01 00:00:00
abstract:OBJECTIVE:We evaluated whether percent time in target range (PTTR), risk of over-anticoagulation [international normalized ratio (INR)>4], and risk of hemorrhage differ by race. As PTTR is a strong predictor of hemorrhage risk, we also determined the influence of PTTR on the risk of hemorrhage by race. PARTICIPANTS AN...
journal_title:Pharmacogenetics and genomics
pub_type: 杂志文章
doi:10.1097/FPC.0000000000000298
更新日期:2017-10-01 00:00:00
abstract:OBJECTIVES:To evaluate whether ABCC2 gene polymorphisms are associated with expression and/or function of the efflux pump. METHODS:We investigated the allele frequency of ABCC2 -24C>T, -23G>A, c.1249G>A, c.1446C>G, c.1457C>T, c.2302C>T, c.2366C>T, c.3542G>T, c.3561G>A, c.3563T>A, c.3972C>T, c.4348G>A, and 4544G>A in 3...
journal_title:Pharmacogenetics and genomics
pub_type: 杂志文章
doi:10.1097/FPC.0b013e3282f974b7
更新日期:2008-04-01 00:00:00
abstract:OBJECTIVES:To assess the influence of individual methylenetetrahydrofolate reductase (MTHFR) C677T and methionine synthase A2756G polymorphisms on the change of serum folate concentration in response to different dosages and durations of folic acid (FA) supplementation in hypertensive Chinese adults. METHODS:A total o...
journal_title:Pharmacogenetics and genomics
pub_type: 杂志文章,多中心研究,随机对照试验
doi:10.1097/FPC.0b013e32834ac5e8
更新日期:2012-06-01 00:00:00
abstract:AIM/OBJECTIVES/BACKGROUND:Hypertension is a risk factor for cardiovascular and kidney disease and is most prevalent in African-American adults. The renin-angiotensin-aldosterone system is integral in blood pressure regulation; angiotensin-converting enzyme inhibitors such as ramipril are first-line treatment options. A...
journal_title:Pharmacogenetics and genomics
pub_type: 杂志文章,随机对照试验
doi:10.1097/FPC.0000000000000154
更新日期:2015-09-01 00:00:00
abstract:OBJECTIVES:Nine different functional UGT1A enzymes are generated from a single UGT1A gene by alternative splicing, with each enzyme having a unique exon 1. SN-38, the active metabolite of the anticancer agent irinotecan, is metabolized by both UGT1A1 and UGT1A9. We aim to characterize the UGT1A9-UGT1A1 haplotypes in As...
journal_title:Pharmacogenetics and genomics
pub_type: 杂志文章
doi:10.1097/01213011-200505000-00004
更新日期:2005-05-01 00:00:00
abstract:OBJECTIVES:The aim of this study was to evaluate the effect of polymorphisms affecting the clopidogrel metabolism (CYP3A4 IVS10+12G/A and CYP2C19*2) and the P2Y12 receptor (P2Y12 T744C) on modulating platelet function in acute coronary syndrome patients on dual antiplatelet treatment. BACKGROUND:Residual platelet reac...
journal_title:Pharmacogenetics and genomics
pub_type: 杂志文章
doi:10.1097/FPC.0b013e3282f1b2be
更新日期:2007-12-01 00:00:00
abstract::Genome-wide studies have identified single nucleotide polymorphisms associated with smoking behaviour and nicotine dependence. Less is known about genetic determinants of smoking cessation, but rs4680 in COMT has recently been shown to explain a substantial proportion of the variation in cessation in the general popul...
journal_title:Pharmacogenetics and genomics
pub_type: 杂志文章
doi:10.1097/FPC.0b013e32832fabf3
更新日期:2009-08-01 00:00:00
abstract:OBJECTIVES:Human novel oxidoreductase 1 (NDOR1) is a diflavin reductase closely related to cytochrome P450 reductase (POR) and nitric oxide synthase (NOS), which are involved in the metabolism of antitumour agents. A variant cDNA sequence of NDOR1, NDOR1 p.518-519ins9 or NDOR1_v1, has been deposited in GenBank (accessi...
journal_title:Pharmacogenetics and genomics
pub_type: 杂志文章
doi:10.1097/01213011-200506000-00002
更新日期:2005-06-01 00:00:00
abstract:BACKGROUND/AIM:Cytochrome P450 oxidoreductase (POR) is required for drug metabolism by all microsomal cytochrome P450 (CYP) enzymes. The aim of this study was to investigate whether single-nucleotide polymorphisms in the POR gene were correlated with interindividual variations in CYP2B6 activity, as measured by bupropi...
journal_title:Pharmacogenetics and genomics
pub_type: 杂志文章
doi:10.1097/FPC.0000000000000190
更新日期:2016-02-01 00:00:00
abstract:BACKGROUND/AIMS:Several single-nucleotide polymorphisms (SNPs) in the catechol-O-methyltransferase (COMT) gene have been associated with the risk of developing Parkinson's disease (PD). We conducted a systematic review and a meta-analysis including all the studies published on PD risk related with COMT SNPs (mainly rs4...
journal_title:Pharmacogenetics and genomics
pub_type: 杂志文章,meta分析,评审
doi:10.1097/FPC.0000000000000056
更新日期:2014-07-01 00:00:00
abstract::CYP2J2 and CYP2C8 metabolize arachidonic acid (AA) to cis-epoxyeicosatrienoic acids (EETs), which play a central role in regulating renal tubular fluid-electrolyte transport and vascular tone. We hypothesized that functionally relevant polymorphisms in the CYP2J2 or CYP2C8 genes influence hypertension risk. We examine...
journal_title:Pharmacogenetics and genomics
pub_type: 杂志文章
doi:10.1097/01213011-200501000-00002
更新日期:2005-01-01 00:00:00
abstract:OBJECTIVES:This study investigated the involvement of ADH4 gene polymorphisms in the susceptibility to alcohol use disorders. METHODS:Thirty-eight single-nucleotide polymorphisms (SNPs) in and around the ADH4 gene were investigated in 136 Italian alcoholics and 276 healthy controls. A new approach based on a bioinform...
journal_title:Pharmacogenetics and genomics
pub_type: 杂志文章
doi:10.1097/FPC.0b013e32834d05c8
更新日期:2012-02-01 00:00:00
abstract:BACKGROUND:For prevention of joint destruction in rheumatoid arthritis, optimal management of therapy with disease-modifying antirheumatic drugs is essential. Pharmacogenomic evidence, if reliable, may be incorporated in the treatment of rheumatoid arthritis to achieve a more efficient activity control with minimized a...
journal_title:Pharmacogenetics and genomics
pub_type: 杂志文章
doi:10.1097/01.fpc.0000236326.80809.b1
更新日期:2007-06-01 00:00:00
abstract::The serotonin (5-HT) 1A receptor has been found to be dysregulated in prefrontal cortex and other brain regions in schizophrenia, and 5-HT1A receptor levels in the amygdala have been related to negative schizophrenia symptoms. We have assessed the impact of the functional C-1019G variant of the 5-HT1A receptor on the ...
journal_title:Pharmacogenetics and genomics
pub_type: 杂志文章,随机对照试验
doi:10.1097/FPC.0b013e328311a917
更新日期:2009-01-01 00:00:00
abstract:OBJECTIVE:Alcohol is detoxified in the liver by oxidizing enzymes that require nicotinamide adenine dinucleotide (NAD+) such that, in the rat, the availability of NAD+ contributes to control voluntary ethanol intake. The UChA and UChB lines of Wistar rats drink low and high amounts of ethanol respectively and differ in...
journal_title:Pharmacogenetics and genomics
pub_type: 杂志文章
doi:10.1097/FPC.0b013e32832dc12a
更新日期:2009-07-01 00:00:00
abstract::Lipid changes with statin treatments vary greatly between individuals for reasons which are largely unknown. This study was performed to examine the genetic determinants of lipid responses to rosuvastatin in Chinese patients. A total of 125 polymorphisms in 61 candidate genes from 386 Chinese patients were analyzed fo...
journal_title:Pharmacogenetics and genomics
pub_type: 杂志文章
doi:10.1097/FPC.0b013e32833de489
更新日期:2010-10-01 00:00:00
abstract:OBJECTIVES:Body weight regulation is under complex control involving the central nervous system and peripheral pathways. The beta-adrenoceptor Galphas protein system plays an important role in heart rate regulation and lipid mobilization suggesting a key role for the stimulatory G protein Galphas in body weight regulat...
journal_title:Pharmacogenetics and genomics
pub_type: 杂志文章,随机对照试验
doi:10.1097/FPC.0b013e3282f49964
更新日期:2008-02-01 00:00:00