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- Aomori, Tohru, et al.
(författare)
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Rapid Single-Nucleotide Polymorphism Detection of Cytochrome P450 (CYP2C9) and Vitamin K Epoxide Reductase (VKORC1) Genes for the Warfarin Dose Adjustment by the SMart-Amplification Process Version 2
- 2009
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Ingår i: Clinical Chemistry. - : Oxford University Press (OUP). - 0009-9147 .- 1530-8561. ; 55:4, s. 804-812
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Polymorphisms of the CYP2C9 (cytochrome P450, family 2, subfamily C, polypeptide 9) gene (CYP2C9*2, CYP2C9*3) and the VKORC1 (vitamin K epoxide reductase complex, subunit 1) gene (-1639G>A) greatly impact the maintenance dose for the drug warfarin. Prescreening patients for their genotypes before prescribing the drug facilitates a faster individualized determination of the proper maintenance dose, minimizing the risk for adverse reaction and reoccurrence of thromboembolic episodes. With current methodologies, therapy can be delayed by several hours to 1 day if genotyping is to determine the loading dose. A simpler and more rapid genotyping method is required. METHODS: We developed a single-nucleotide polymorphism (SNP)-detection assay based on the SMart Amplification Process version 2 (SMAP 2) to analyze CYP2C9*2, CYP2C9*3, and VKORC1 -1639G>A polymorphisms. Blood from consenting participants was used directly in a closed-tube real-time assay without DNA purification to obtain results within 1 h of blood collection. RESULTS: We analyzed 125 blood samples by both SMAP 2 and PCR-RFLP methods. The results showed perfect concordance. CONCLUSIONS: The results validate the accuracy of the SMAP 2 for determination of SNPs critical to personalized warfarin therapy. SMAP 2 offers speed, simplicity of sample preparation, the convenience of isothermal amplification, and assay-design flexibility, which are significant advantages over conventional genotyping technologies. In this example and other clinical scenarios in which genetic testing is required for immediate and better-informed therapeutic decisions, SMAP 2-based diagnostics have key advantages.
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| 3. |
- Artibani, Walter, et al.
(författare)
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EAU Policy on Live Surgery Events.
- 2014
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Ingår i: European Urology. - : Elsevier BV. - 1873-7560 .- 0302-2838. ; 66:1, s. 87-97
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Forskningsöversikt (refereegranskat)abstract
- Live surgery is an important part of surgical education, with an increase in the number of live surgery events (LSEs) at meetings despite controversy about their real educational value, risks to patient safety, and conflicts of interest.
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| 4. |
- Canaparo, Roberto, et al.
(författare)
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Expression of cytochromes P450 3A and P-glycoprotein in human large intestine in paired tumour and normal samples
- 2007
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Ingår i: Basic & Clinical Pharmacology & Toxicology. - : Wiley. - 1742-7843 .- 1742-7835. ; 100:4, s. 240-248
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Tidskriftsartikel (refereegranskat)abstract
- Our objective was to investigate the expression of different cytochromes P450 3A (CYP3A4, CYP3A5, and CYP3A7) and P-glycoprotein (ABCBI) genes along the human large intestine in paired tumour and normal samples. Real-time reverse transcriptase-polymerase chain reaction was used to measure CYP3A4-, CYP3A5-, CYP3A7- and ABCB1-specific mRNA expression, and Western blot analysis was used to measure membrane protein levels of CYP3A4/7, CYP3A5 and P-glycoprotein. Levels of mRNA and membrane protein fractions in the large intestine were compared with those of normal human liver. The mRNA expressions of CYP3A4, CYP3A5, CYP3A7 and ABCB1 in the large intestine were found to be highly variable, but overall the levels were significantly lower than those measured in liver (P < 0.0001, P < 0.00 1, P < 0.0001 and P < 0.01, respectively). At the membrane protein level, CYP3A4/7 was detected in all large intestine samples examined and the levels were substantially higher than those of the liver (P < 0.01). Although expression of CYP3A5 was detected in all large intestine samples, in most the levels were too low to allow quantification. P-glycoprotein was readily detected at levels slightly higher than those of liver (P < 0.05). Comparison between paired samples of normal and tumour in large intestine showed no significant differences in either the mRNA or membrane protein levels of these genes. In conclusion, this work suggests a potential role of the large intestine in the absorption and metabolism of xenobiotics and nutrients and no difference in the CYP3A and P-glycoprotein membrane protein fractions and mRNA expression between normal and tumour tissues.
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- Elens, Laure, et al.
(författare)
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Genetic Predisposition to Poor Opioid Response in Preterm Infants : Impact of KCNJ6 and COMT Polymorphisms on Pain Relief after Endotracheal Intubation
- 2016
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Ingår i: Therapeutic Drug Monitoring. - 0163-4356 .- 1536-3694. ; 38:4, s. 525-533
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Tidskriftsartikel (refereegranskat)abstract
- Background: Single-nucleotide polymorphisms in genes involved in pain control might predispose to exaggerated sensitivity or difference in opioid analgesic effect. The relevance of the KCNJ6 -1250G>A (rs6517442, c.-1787G>A) and the catecholamine-O-methyltransferase (COMT) c.472G>A (rs4680, Val 158 Met) single-nucleotide polymorphisms were studied in preterm infants needing intubation and randomized to a premedication strategy including remifentanil (n 17) or morphine (n 17). Methods: Pain was scored with Astrid Lindgren and Lund Children's Hospital Pain Assessment Scale every 30 minutes for 6 hours. The pain relief provided by the opioids was compared between the different KCNJ6 and COMT genotypes. Results: Infants homozygous for the KCNJ6 -1250A allele had an increased duration after intubation to achieve a score indicating no pain compared with infants with the A/G or G/G genotypes (182 ± 30, 109 ± 29, and 60 ± 21 minutes, respectively; Logrank 7.5, P 0.006). Similarly, the duration was increased in individuals with the COMT Val/Val alleles compared with Val/Met and Met/Met (285 ± 37, 137 ± 25, and 63 ± 15 minutes, respectively; Logrank 14.4, P 0.0021). Cox proportional hazards analysis confirmed that the variation in both genes was independently associated with susceptibility to respond to therapy. Conclusion: We conclude that the KCNJ6 -1250A and COMT 158 Val alleles are predisposing preterm newborns to diminished opioid-induced pain relief.
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- Eriksson, Anna-Lena, 1971, et al.
(författare)
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SHBG gene promoter polymorphisms in men are associated with serum sex hormone-binding globulin, androgen and androgen metabolite levels, and hip bone mineral density.
- 2006
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Ingår i: The Journal of clinical endocrinology and metabolism. - : The Endocrine Society. - 0021-972X .- 1945-7197. ; 91:12, s. 5029-37
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Tidskriftsartikel (refereegranskat)abstract
- CONTEXT: SHBG regulates free sex steroid levels, which in turn regulate skeletal homeostasis. Twin studies have demonstrated that genetic factors largely account for interindividual variation in SHBG levels. Glucuronidated androgen metabolites have been proposed as markers of androgenic activity. OBJECTIVE: Our objective was to investigate whether polymorphisms in the SHBG gene promoter [(TAAAA)(n) microsatellite and rs1799941 single-nucleotide polymorphism] are associated with serum levels of SHBG, sex steroids, or bone mineral density (BMD) in men. DESIGN AND STUDY SUBJECTS: We conducted a population-based study of two cohorts of Swedish men: elderly men (MrOS Sweden; n congruent with 3000; average age, 75.4 yr) and young adult men (GOOD study; n = 1068; average age, 18.9 yr). MAIN OUTCOME MEASURES: We measured serum levels of SHBG, testosterone, estradiol, dihydrotestosterone, 5alpha-androstane-3alpha,17beta-diol glucuronides, androsterone glucuronide, and BMD determined by dual-energy x-ray absorptiometry. RESULTS: In both cohorts, (TAAAA)(n) and rs1799941 genotypes were associated with serum levels of SHBG (P < 0.001), dihydrotestosterone (P < 0.05), and 5alpha-androstane-3alpha,17beta-diol glucuronides (P < 0.05). In the elderly men, they were also associated with testosterone and BMD at all hip bone sites. The genotype associated with high levels of SHBG was also associated with high BMD. Interestingly, male mice overexpressing human SHBG had increased cortical bone mineral content in the femur, suggesting that elevated SHBG levels may cause increased bone mass. CONCLUSIONS: Our findings demonstrate that polymorphisms in the SHBG promoter predict serum levels of SHBG, androgens, and glucuronidated androgen metabolites, and hip BMD in men.
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| 9. |
- Hakkola, Jukka, et al.
(författare)
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Expression of CYP1B1 in human adult and fetal tissues and differential inducibility of CYP1B1 and CYP1A1 by Ah-receptor ligands in human placenta and cultured cells
- 1997
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Ingår i: Carcinogenesis. - 0143-3334 .- 1460-2180. ; 18:2, s. 391-7
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Tidskriftsartikel (refereegranskat)abstract
- Expression of the Ah receptor-regulated cytochrome P4501B1 (CYP1B1) gene was studied in human adult and fetal tissues and cells in culture by reverse transcriptase-coupled polymerase chain reaction (RT-PCR). In adults, CYP1B1 mRNA was detected in liver, lymphocytes, cells of bronchoalveolar lavage samples and uterine endometrium, but not in lung. The level of expression was very low in adult liver and only three out of six fetal livers expressed CYP1B1. Extrahepatic fetal tissues, especially brains and kidneys, expressed high levels of CYP1B1. CYP1B1 mRNA was constitutively detected at a low level in first trimester and full-term placental samples. A competitive RT-PCR assay was developed to assess the regulation of CYP1B1. CYP1B1 mRNA was not induced in placenta by maternal cigarette smoking. Inducibility of CYP1B1 in cells in culture by the Ah receptor ligand 2,3,7,8-tetrachlorodibenzo-p-dioxin was studied in primary fibroblasts and chorion carcinoma cell line JEG-3 having different CYP1A1 induction properties. Inducibility of CYP1B1 was found to be regulated independently from CYP1A1. In JEG-3 cells CYP1A1 mRNA was induced up to 9000-fold, while the expression of CYP1B1 was not affected. Expression of Ah receptor and Ah receptor nuclear translocator (regulators of the CYP1 family) was determined in human placenta and in the JEG-3 cell line. Expression of these transcription factors was found neither to be co-regulated nor affected by Ah receptor ligands. This study provides evidence that in addition to the Ah receptor complex, other cell-specific factors modulate the response of CYP1B1 and CYP1A1 to Ah receptor ligands.
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| 10. |
- Hedenmalm, Karin, 1963-, et al.
(författare)
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Increased liability of tramadol-warfarin interaction in individuals with mutations in the cytochrome p450 2D6 gene
- 2004
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Ingår i: European Journal of Clinical Pharmacology. - : Springer Science and Business Media LLC. - 0031-6970 .- 1432-1041. ; 60:5, s. 369-372
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Tidskriftsartikel (refereegranskat)abstract
- Objective This study aimed to investigate the importance of cytochrome P450 enzymes for the reported interaction between tramadol and warfarin.Materials and methods Cases of suspected interaction between tramadol and warfarin resulting in International Normalised Ratios increases that were reported to the Swedish Adverse Drug Reactions Advisory Committee until March 2003 were included. Ten cases had been genotyped for known polymorphisms of CYP2D6, CYP2C9 and CYP2C19.Results Seven of ten patients carried defective CYP2D6 alleles (population prevalence 42.2%) (one-sided binomial test, P=0.07). A further patient received concomitant drug treatments that may have resulted in CYP2D6 enzyme inhibition.Conclusion The liability to an interaction between tramadol and warfarin may be related to the CYP2D6 activity.
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