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ABCB1 gene polymorphisms are associated with fatal intoxications involving venlafaxine but not citalopram.

https://arctichealth.org/en/permalink/ahliterature115364
Source
Int J Legal Med. 2013 May;127(3):579-86
Publication Type
Article
Date
May-2013
Author
L. Karlsson
H. Green
A L Zackrisson
F. Bengtsson
I. Jakobsen Falk
B. Carlsson
J. Ahlner
F C Kugelberg
Author Affiliation
Division of Drug Research, Clinical Pharmacology, Department of Medical and Health Sciences, Linköping University, Linköping, Sweden.
Source
Int J Legal Med. 2013 May;127(3):579-86
Date
May-2013
Language
English
Publication Type
Article
Keywords
Adolescent
Adult
Aged
Aged, 80 and over
Antidepressive Agents, Second-Generation - poisoning
Autopsy
Case-Control Studies
Citalopram - poisoning
Cyclohexanols - poisoning
Drug Overdose - genetics
Female
Forensic Genetics
Humans
Male
Middle Aged
P-Glycoprotein - genetics
Polymorphism, Single Nucleotide
Sweden
Abstract
P-glycoprotein (P-gp), encoded by the ABCB1/MDR1 gene, is a drug transporter at the blood-brain barrier. Several polymorphisms in the ABCB1 gene are known to affect the activity and/or expression of P-gp, thereby influencing the treatment response and toxicity of P-gp substrates like citalopram and venlafaxine. In this study, we aimed to investigate the frequency of ABCB1 genotypes in forensic autopsy cases involving these two antidepressants. Further, the distribution of ABCB1 genotypes in deaths related to intoxication was compared to cases not associated to drug intoxication. The study included 228 forensic autopsy cases with different causes and manners of deaths. The ABCB1 single nucleotide polymorphisms (SNPs) G1199A, C1236T, C3435T and G2677T/A for these individuals were determined. The SNPs C1236T and C3435T in venlafaxine-positive cases were significantly different between the intoxication cases and non-intoxications. This was not seen for cases involving citalopram, indicating that the effect of genetic variants might be substrate specific. This novel finding should, however, be confirmed in future studies with larger number of cases.
PubMed ID
23515680 View in PubMed
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ABCB1 haplotypes differentially affect the pharmacokinetics of the acid and lactone forms of simvastatin and atorvastatin.

https://arctichealth.org/en/permalink/ahliterature152450
Source
Clin Pharmacol Ther. 2008 Oct;84(4):457-61
Publication Type
Article
Date
Oct-2008
Author
J E Keskitalo
K J Kurkinen
P J Neuvoneni
M. Niemi
Author Affiliation
Department of Clinical Pharmacology, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland.
Source
Clin Pharmacol Ther. 2008 Oct;84(4):457-61
Date
Oct-2008
Language
English
Publication Type
Article
Keywords
Area Under Curve
Cross-Over Studies
Female
Finland
Half-Life
Haplotypes
Heptanoic Acids - pharmacokinetics
Humans
Hydroxymethylglutaryl-CoA Reductase Inhibitors - pharmacokinetics
Lactones - pharmacokinetics
Male
P-Glycoprotein - genetics
Polymorphism, Single Nucleotide
Pyrroles - pharmacokinetics
Simvastatin - pharmacokinetics
Abstract
ABCB1 haplotypes were determined in 534 healthy Finnish volunteers, of whom 24 participated in a pharmacokinetic study on simvastatin and atorvastatin. The frequencies of occurrence of haplotypes c.1236T-c.2677T-c.3435T and c.1236C-c.2677G-c.3435C were 42.7 and 34.4%, respectively. The simvastatin acid AUC(0-12h) was 60% larger, the atorvastatin AUC(0-infinity) 55% larger, and the atorvastatin half-life 24% longer in subjects with the ABCB1 TTT/TTT genotype (n = 12) than in those with the CGC/CGC genotype (n = 12) (P
PubMed ID
19238649 View in PubMed
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The ABCB1, rs9282564, AG and TT genotypes and the COMT, rs4680, AA genotype are less frequent in deceased patients with opioid addiction than in living patients with opioid addiction

https://arctichealth.org/en/permalink/ahliterature280048
Source
Basic Clin Pharmacol Toxicol. 2016 Oct;119(4):381-8
Publication Type
Article
Date
Oct-2016
Author
Christoffersen DJ
Damkier P
Feddersen S
Möller S
Thomsen JL
Brasch-Andersen C
Brøsen K
Source
Basic Clin Pharmacol Toxicol. 2016 Oct;119(4):381-8
Date
Oct-2016
Language
English
Publication Type
Article
Keywords
Adolescent
Adult
Aged
Catechol O-Methyltransferase - genetics - metabolism
Cohort Studies
Death, Sudden - etiology
Denmark
Female
Genetic Association Studies
Heterozygote
Homozygote
Humans
Male
Methadone - blood - toxicity
Middle Aged
Morphine - blood - toxicity
Morphine Dependence - genetics - metabolism - mortality - physiopathology
Narcotics - blood - toxicity
P-Glycoproteins - genetics - metabolism
Polymorphism, Single Nucleotide
Young Adult
Abstract
Sudden death due to acute intoxication occurs frequently in patients with opioid addiction (OA). To examine whether certain genotypes were associated with this, we examined the frequencies of 29 SNPs located in candidate genes related to opioid pharmacology: ABCB1, OPRM1, UGT2B7, CYP3A5, CYP2B6, CYP2C19, CYP2D6, COMT, KCNJ6 and SCN9A in 274 deceased patients with OA (DOA), 309 living patients with OA (LOA) and in 394 healthy volunteers (HV). The main hypothesis of the study was that subjects homozygous for the variant 3435T in ABCB1 (rs1045642) occur more frequently in DOA than in LOA and HV because morphine and methadone more readily cross the blood barrier in these subjects due to a lower efflux transporter activity of the ABCB1 (p-glycoprotein) transporter. Our results did not support this hypothesis, because no statistically significant difference (p = 0.506) in the frequency of the TT genotype of rs1045642 was observed between the DOA, LOA and HV cohorts. However, for another ABCB1 variant, rs9282564, we found that the frequencies of the AG and TT genotypes were 13, 21 and 25% in DOA, LOA and HV, respectively, and after correcting for age, sex and multiple testing, the differences between DOA and LOA were statistically significantly different (p = 0.027). The COMT rs4680 AA genotype frequencies were 25%, 35% and 31% in DOA, LOA and HV, respectively, and the difference between DOA and LOA was also statistically significant (p = 0.0028). In conclusion, this study generated two hypotheses suggesting possible associations of a reduced risk of death and carrying, respectively, the ABCB1 rs9282564 AG and TT genotypes and the COMT rs4680 AA genotype among patients with OA. These findings should be confirmed in independent cohorts, and if a causal relationship between these variants and fatal poisoning in OA is confirmed, then it may be possible at least in theory to personalize prevention of sudden death in this patient group.
PubMed ID
27061230 View in PubMed
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ABCB4 sequence variations in young adults with cholesterol gallstone disease.

https://arctichealth.org/en/permalink/ahliterature91197
Source
Liver Int. 2009 May;29(5):743-7
Publication Type
Article
Date
May-2009
Author
Nakken Karl Esten
Labori Knut Jørgen
Rødningen Olaug K
Nakken Sigve
Berge Knut E
Eiklid Kristin
Raeder Morten G
Author Affiliation
Institute for Experimental Medical Research, Ullevaal University Hospital, Oslo, Norway. esten.nakken@medisin.uio.no
Source
Liver Int. 2009 May;29(5):743-7
Date
May-2009
Language
English
Publication Type
Article
Keywords
Adolescent
Adult
Cholesterol - chemistry
Female
Gallstones - genetics
Genetic Variation
Humans
Male
Mutation - genetics
Norway
P-Glycoproteins - genetics
Abstract
BACKGROUND AND AIMS: Mutations in the gene encoding the ABCB4 [adenosine triphosphate (ATP)-binding cassette, sub-family B (MDR/TAP), member 4] transporter lower phosphatidylcholine output into bile and contribute to cholesterol gallstone formation by decreasing the solubility of cholesterol in bile. Mutations in ABCB4 have been identified in patients with low phospholipid-associated cholelithiasis. The aim of the present study was to determine the types and frequencies of ABCB4 mutations in cholecystectomized patients aged T/p.R1046X). These two mutations are considered detrimental to ABCB4 protein function. In addition, six missense mutations were found in the ABCB4 gene, and three of these were only present in patients. CONCLUSION: In our study,
PubMed ID
19018976 View in PubMed
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[Analysis of genetic predisposition to pulmonary tuberculosis in native Russians].

https://arctichealth.org/en/permalink/ahliterature144799
Source
Genetika. 2010 Feb;46(2):262-71
Publication Type
Article
Date
Feb-2010
Author
O A Gra
Zh M Kozhekbaeva
V I Litvinov
Source
Genetika. 2010 Feb;46(2):262-71
Date
Feb-2010
Language
Russian
Publication Type
Article
Keywords
Adult
Aged
Aged, 80 and over
Alleles
Cation Transport Proteins - genetics
Cohort Studies
Cytochrome P-450 Enzyme System - genetics
Female
Gene Frequency - genetics
Genetic Predisposition to Disease - epidemiology - genetics
Genotype
Glutathione Transferase - genetics
Humans
Male
Middle Aged
Moscow - epidemiology - ethnology
P-Glycoprotein - genetics
Tuberculosis, Pulmonary - epidemiology - genetics
Abstract
Tuberculosis (TB) is one of the most important concerns of public health. There is evidence suggesting that genetic status is responsible for predisposition to infectious diseases including TB. To determine genetic risk factors of TB development, the frequencies of polymorphisms of genes CYP1A1, CYP2D6, CYP2C9, CYP2C 19, GSTT1, GSTM1, NAT2, MDR1, and NRAMP1 in 73 TB patients and 352 healthy individuals were determined by allele-specific hybridization using microarray technology. The TB patients have shown a significant increase in the frequency of the null GSTT1 genotype (OR = 3.26, 95% CI = 1.91 - 5.55, p = = 0.000028) as well as the double null GSTT1/GSTM1 genotype (OR = 4.05, 95% CI = 2.14 -7.65, p = = 0.000034) compared to the group of healthy donors. It was shown that the NAT2*5/*5 genotype in combination with the "null" GSTT1 and the double "null" GSTT1/GSTM1 genotypes was observed significantly more often in the TB patients than in the control sample. Thus the examined GSTT1, GSTM1 and NAT2 gene polymorphisms may potentially alter the risk of TB development in ethnic Russians and are of interest for further research using larger cohorts of patients.
PubMed ID
20297661 View in PubMed
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Association of MDR1 genotypes with susceptibility to colorectal cancer in older non-smokers.

https://arctichealth.org/en/permalink/ahliterature166249
Source
Eur J Clin Pharmacol. 2007 Jan;63(1):9-16
Publication Type
Article
Date
Jan-2007
Author
Elena Osswald
Andreas Johne
Gabriele Laschinski
Farhad Arjomand-Nahad
Uwe Malzahn
Julia Kirchheiner
Thomas Gerloff
Christian Meisel
Przemyslaw M Mrozikiewicz
Jury Chernov
Ivar Roots
Karla Köpke
Author Affiliation
Institute of Clinical Pharmacology, Charité-Universitätsmedizin Berlin, Campus Mitte, Humboldt University of Berlin, Berlin, Germany.
Source
Eur J Clin Pharmacol. 2007 Jan;63(1):9-16
Date
Jan-2007
Language
English
Publication Type
Article
Keywords
Adult
Aged
Aging
Alcohol Drinking - adverse effects
Case-Control Studies
Colorectal Neoplasms - etiology - genetics - pathology
Female
Genetic Predisposition to Disease
Genotype
Humans
Life Style
Male
Middle Aged
P-Glycoprotein - genetics
Polymorphism, Genetic
Risk factors
Russia
Smoking - adverse effects
Abstract
The multidrug resistance gene 1 (MDR1) seems to play a role in the carcinogenesis of colorectal tumors. The importance of MDR1 SNPs 2677G > T/A in exon 21 and 3435C > T in exon 26 for cancer susceptibility, however, has not yet been clearly defined.
Two hundred and eighty-five colorectal cancer patients and 275 controls from five hospitals in the European part of Russia were genotyped for the polymorphisms -129T > C (rs3213619) in exon 1b, 2677G > T/A (rs2032582), and 3435C > T (rs1045642) in this population-based case-control study. Genotype-phenotype analysis was performed with simultaneous consideration of lifestyle risk factors.
Our analysis confirmed the preponderate impact of smoking on colorectal cancer development. The risk of heavy smokers (>/=60 pack years) to develop colorectal cancer by far exceeded that of lifelong non-smokers (OR = 3.9, 95% CI: 1.4 to 10.6). Smoking is a more potent risk factor than is the genetic influence of MDR1 in our study. However, a smoking and age-stratified analysis, revealed a statistically significant association between MDR1 genotypes and colorectal cancer in life-long non-smokers with an age > or =63 years (the median age in our sample). The association was stronger for rectal cancer than for colon cancer. Patients who carried the genotypes (-129TT; 2677GG; 3435CC) or (-129TT; 2677TT; 3435TT) developed more frequently colorectal cancer than others (OR = 3.9; 95% CI: 2.0 to 7.7).
Our results show that the interaction of genetic and lifestyle risk factors should be taken into account to elucidate the genetic influence of MDR1 variability on cancer susceptibility.
PubMed ID
17146660 View in PubMed
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Cyclooxygenase-2, multidrug resistance 1, and breast cancer resistance protein gene polymorphisms and inflammatory bowel disease in the Danish population.

https://arctichealth.org/en/permalink/ahliterature91878
Source
Scand J Gastroenterol. 2009;44(1):65-73
Publication Type
Article
Date
2009
Author
Østergaard Mette
Ernst Anja
Labouriau Rodrigo
Dagiliené Enrika
Krarup Henrik B
Christensen Mariann
Thorsgaard Niels
Jacobsen Bent A
Tage-Jensen Ulrik
Overvad Kim
Autrup Herman
Andersen Vibeke
Author Affiliation
Medical Department, Viborg Regional Hospital, Viborg.
Source
Scand J Gastroenterol. 2009;44(1):65-73
Date
2009
Language
English
Publication Type
Article
Keywords
ATP-Binding Cassette Transporters - genetics
Adult
Alleles
Case-Control Studies
Colitis, Ulcerative - genetics
Crohn Disease - genetics
Cyclooxygenase 2 - genetics
Denmark
Female
Genotype
Humans
Inflammatory Bowel Diseases - genetics
Male
Middle Aged
Neoplasm Proteins - genetics
Odds Ratio
P-Glycoprotein - genetics
Phenotype
Polymorphism, Genetic
Polymorphism, Single Nucleotide
Abstract
OBJECTIVE: Crohn's disease (CD) and ulcerative colitis (UC) are characterized by an impaired mucosal defence to normal constituents of the intestinal flora and a dysregulated inflammatory response. The purpose of the study was to investigate whether single nucleotide polymorphisms (SNPs) in genes involved in these processes were associated with CD and UC. MATERIAL AND METHODS: Allele frequencies of the cyclooxygenase 2 (COX-2/PTGS2/PGHS2) G-765C and breast cancer resistance protein (BCRP/ABCG2) C421A as well as allele and haplotype frequencies of multidrug resistance 1 (MDR1, ABCB1) SNPs G2677T/A, C3435T and G-rs3789243-A (intron 3) were assessed in a Danish case-control study comprising 373 CD and 541 UC patients and 796 healthy controls. RESULTS: Carriers of the homozygous COX-2 and MDR1 intron 3 variant had a relatively high risk of CD, odds ratio (95% CI) (OR (95% CI))=2.86 ((1.34-5.88) p=0.006) and 1.39 ((0.99-1.92) p=0.054), respectively, and for UC of 2.63 ((1.33-5.26) p=0.005) and 1.28 ((0.96-1.51) p=0.093), respectively, assuming complete dominance. No association was found for BCRP or other MDR1 SNPs, or for selected MDR1 haplotypes. No effect-modification of smoking habit at the time of diagnosis was found. CONCLUSIONS: An effect of the COX-2 polymorphism on both CD and UC was shown which is compatible with the presence of a recessive allele in linkage equilibrium with the SNP marker in the COX-2 gene. The polymorphism located in intron 3 of the MDR1 gene showed a weak association with CD, and a marginally suggestive association with UC.
PubMed ID
18819034 View in PubMed
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Genetic evidence of heterogeneity in intrahepatic cholestasis of pregnancy.

https://arctichealth.org/en/permalink/ahliterature184996
Source
Gut. 2003 Jul;52(7):1025-9
Publication Type
Article
Date
Jul-2003
Author
M. Savander
A. Ropponen
K. Avela
N. Weerasekera
B. Cormand
M-L Hirvioja
S. Riikonen
O. Ylikorkala
A-E Lehesjoki
C. Williamson
K. Aittomäki
Author Affiliation
Department of Medical Genetics and Folkhälsan Institute of Genetics, Biomedicum Helsinki, University of Helsinki, Helsinki, Finland.
Source
Gut. 2003 Jul;52(7):1025-9
Date
Jul-2003
Language
English
Publication Type
Article
Keywords
ATP-Binding Cassette Transporters - genetics
Adult
Bile Acids and Salts - blood
Cholestasis, Intrahepatic - epidemiology - genetics
Family Health
Female
Finland - epidemiology
Genes, Dominant - genetics
Genetic Heterogeneity
Genetic Linkage - genetics
Genotype
Haplotypes - genetics
Humans
Incidence
P-Glycoproteins - genetics
Pedigree
Pregnancy
Pregnancy Complications - epidemiology - etiology
Prospective Studies
Transaminases - blood
Abstract
The aim of this study was to investigate the genetic aetiology of intrahepatic cholestasis of pregnancy (ICP) and the impact of known cholestasis genes (BSEP, FIC1, and MDR3) on the development of this disease.
Sixty nine Finnish ICP patients were prospectively interviewed for a family history of ICP, and clinical features were compared in patients with familial ICP (patients with a positive family history, n=11) and sporadic patients (patients with no known family history of ICP, n=58). For molecular genetic analysis, 16 individuals from two independently ascertained Finnish ICP families were genotyped for the flanking markers for BSEP, FIC1, and MDR3.
The pedigree structures in 16% (11/69) of patients suggested dominant inheritance. Patients with familial ICP had higher serum aminotransferase levels and a higher recurrence risk (92% v 40%). Both segregation of haplotypes and multipoint linkage analysis excluded BSEP, FIC1, and MDR3 genes in the studied pedigrees. Additionally, the MDR3 gene, previously shown to harbour mutations in ICP patients, was negative for mutations when sequenced in four affected individuals from the two families.
These results support the hypothesis that the aetiology of ICP is heterogeneous and that ICP is due to a genetic predisposition in a proportion of patients. The results of molecular genetic analysis further suggest that the previously identified three cholestasis genes are not likely to be implicated in these Finnish ICP families with dominant inheritance.
Notes
Cites: Gastroenterology. 1999 Dec;117(6):1370-910579978
Cites: Acta Obstet Gynecol Scand. 1964;43:SUPPL 5:1-13014147595
Cites: Gastroenterology. 2001 May;120(6):1448-5811313315
Cites: Gastroenterology. 2001 May;120(6):1459-6711313316
Cites: Gastroenterology. 2001 May;120(6):1549-5211313328
Cites: Hepatology. 2001 Oct;34(4 Pt 1):768-7511584374
Cites: Am J Dis Child. 1969 Jan;117(1):112-245762004
Cites: Acta Med Scand. 1974 Jun;195(6):459-634835153
Cites: Ann Chir Gynaecol Fenn. 1975;64(3):155-641217841
Cites: Gut. 1976 Sep;17(9):709-13976812
Cites: Ann Intern Med. 1978 Apr;88(4):487-93637428
Cites: Gastroenterology. 1983 Jul;85(1):175-96852450
Cites: Int J Gynaecol Obstet. 1984 Apr;22(2):91-46145644
Cites: Acta Obstet Gynecol Scand. 1986;65(2):107-133727939
Cites: Gastroenterology. 1987 Sep;93(3):643-92956151
Cites: Am J Epidemiol. 1987 Nov;126(5):912-213310613
Cites: Scand J Gastroenterol. 1987 Nov;22(9):1089-943321395
Cites: Br J Obstet Gynaecol. 1988 Nov;95(11):1137-433207643
Cites: Clin Genet. 1993 Jun;43(6):315-78370153
Cites: Am J Obstet Gynecol. 1994 Mar;170(3):890-58141222
Cites: J Pediatr Gastroenterol Nutr. 1994 Feb;18(2):134-417912266
Cites: Hum Mol Genet. 1995 Jun;4(6):1049-537655458
Cites: Am J Hum Genet. 1996 Jun;58(6):1347-638651312
Cites: Proc Natl Acad Sci U S A. 1998 Jan 6;95(1):282-79419367
Cites: Nat Genet. 1998 Mar;18(3):219-249500542
Cites: Nat Genet. 1998 Nov;20(3):233-89806540
Cites: Lancet. 1999 Jan 16;353(9148):210-19923886
Cites: J Hepatol. 1999 Aug;31(2):377-8110453956
Cites: Hum Mol Genet. 2000 May 1;9(8):1209-1710767346
PubMed ID
12801961 View in PubMed
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Genetic polymorphism of cytochrome P450s and P-glycoprotein in the Finnish population.

https://arctichealth.org/en/permalink/ahliterature162434
Source
Fundam Clin Pharmacol. 2007 Aug;21(4):379-86
Publication Type
Article
Date
Aug-2007
Author
Johanna Hilli
Anders Rane
Stefan Lundgren
Leif Bertilsson
Kari Laine
Author Affiliation
Department of Pharmacology, Drug Development and Therapeutics, University of Turku, Itäinen Pitkäkatu 4B, 3rd floor, FIN-20520 Turku, Finland. johanna.hilli@utu.fi
Source
Fundam Clin Pharmacol. 2007 Aug;21(4):379-86
Date
Aug-2007
Language
English
Publication Type
Article
Keywords
Adolescent
Adult
Aged
Aryl Hydrocarbon Hydroxylases - genetics
Cytochrome P-450 CYP1A2 - genetics
Cytochrome P-450 Enzyme System - genetics
Female
Finland
Gene Frequency
Genotype
Humans
Male
Middle Aged
Mixed Function Oxygenases - genetics
P-Glycoprotein - genetics
Polymorphism, Genetic
Abstract
The objective of this study was to investigate the genetic polymorphism of selected cytochrome P450 (CYP) enzymes and ABCB1 (encoding P-glycoprotein) of central importance with regard to the disposition of clinically used drugs in the Finnish population and to compare the results to pre-existing data from Caucasian populations. A random sample of 449 Finns was studied. Single nucleotide polymorphisms (SNPs) were genotyped using blood-derived genomic DNA and 5'-nuclease assays. We found that the allele frequencies of CYP1A2 SNP g.-163C>A, CYP2C8*3, CYP2C9*2, CYP2C9*3 and CYP2C19*2 were similar to those seen in other Caucasian populations. However, the allelic frequency of the variant ABCB1 SNP c.3435C>T allele was lower than previously reported. The frequency of the homozygous CYP3A5*1 expression was significantly higher than expected based on Hardy-Weinberg calculations (observed n = 8 vs. expected n = 3, P = 0.01). Other genotype frequencies corresponded to the expected values. The strong linkage between the CYP2C8*3 and the CYP2C9*2 alleles was confirmed in this study and the number of individuals with the rare haplotype CYP2C8*3*3/CYP2C9*2*2 was higher than expected. We conclude that the frequency of mutated CYP alleles in Finns were in agreement with earlier findings in Caucasian populations, but a lower frequency of the ABCB1 variant allele 3435T corresponding to that reported in Asian populations was found. The higher than expected frequency of the CYP3A5*1*1 genotype and the CYP2C8*3*3/CYP2C9*2*2 haplotype may influence the response to treatment with drugs metabolized by these enzymes.
PubMed ID
17635176 View in PubMed
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Identification of in vivo P-glycoprotein mRNA decay intermediates in normal liver but not in liver tumors.

https://arctichealth.org/en/permalink/ahliterature17174
Source
J Cell Physiol. 2005 Aug;204(2):638-45
Publication Type
Article
Date
Aug-2005
Author
Chow H Lee
Vicki E Rehaume
Janis Shandro
Author Affiliation
Chemistry Program, University of Northern British Columbia, British Columbia, Canada. leec@unbc.ca
Source
J Cell Physiol. 2005 Aug;204(2):638-45
Date
Aug-2005
Language
English
Publication Type
Article
Keywords
Animals
Base Sequence
Liver - metabolism
Liver Neoplasms - metabolism
Male
Molecular Sequence Data
P-Glycoproteins - genetics
Polymerase Chain Reaction - methods
RNA, Messenger - metabolism
Rats
Rats, Inbred F344
Research Support, Non-U.S. Gov't
Abstract
Post-transcriptional regulation at the level of mRNA stability is one important mechanism for over-expression of P-glycoprotein (Pgp) genes observed in cultured cells and in animals. A previous study has shown that mRNA half-lives for Pgp genes in normal liver were less than 2 h, in contrast to greater than 12 h measured in a transplantable liver tumor line. This lower turnover rate of Pgp mRNA may, in large part, contribute to the abundance of Pgp mRNA in liver tumors. The current study sought to investigate the underlying mechanism for the lower turnover rate of Pgp2 mRNA previously determined in liver tumors. As a first approach, we set out to understand the Pgp2 mRNA decay in both normal liver and liver tumors by first identifying and characterizing Pgp2 mRNA degradation intermediates. In this study, we showed that the sensitive ligation-mediated polymerase chain reaction (LM-PCR) method can be used to detect a homogenous pool of in vitro transcribed RNA down to 0.4 ng. By employing gene-specific primers in the LM-PCR method, we successfully identified four Pgp2 mRNA decay intermediates in normal liver. All four decay intermediates detected correspond to the 5' coding region of Pgp2 mRNA, and surprisingly no decay intermediates which correspond to 3' untranslated region, 3' coding region or middle coding region were found using LM-PCR. The identified decay intermediates are unique to the normal liver as they were absent or present at very low level in all three liver tumor samples analyzed. This observation supports our previous findings that the Pgp mRNA turnover rate is lower in liver tumors than in normal liver. These findings have implications for our understanding of the regulation of Pgp mRNA turnover in normal and malignant tissues.
PubMed ID
15744753 View in PubMed
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24 records – page 1 of 3.