M Schwab

..Therefore, we investigated the role of DNA methylation in the transcriptional regulation of the family members SLC22A1/OCT1, SLC22A2/OCT2 and SLC22A3/OCT3 in HCC...

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..An association of this triad of findings no longer appears to be accidental...

..Potential implications of MDR1 polymorphisms for drug disposition, drug effects, and disease risk are discussed...

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..The implementation of pharmacogenomics into clinical practise is a momentous future challenge that requires the establishment of interdisciplinary networks and professional organizations...

..This case illustrates that the use of trade names, omitting the international nonproprietary names of the active moiety, carries the risk of serious adverse drug events by overdose...

..Tioguanine (thioguanine) therapy results in much higher levels of 6-thioguanine-nucleotide levels when compared with azathioprine or mercaptopurine...

..These data warrant further studies to elucidate the drug-interaction potential of metamizole, especially in patients with long-term treatment...

..Additionally, DHPLC allows a simultaneous screening for novel genetic variability in the TPMT gene...

..Tioguanine may offer an alternative for immunosuppression in chronic active Crohn's disease. Recently, we have shown that tioguanine is effective in inducing rapid remission...

..This study tests the hypothesis that CYP2C19 wild type ( wt/wt ) in white patients is also associated with a higher probability of treatment failure...

..No significant associations were found between OATP-B, MRP2 or MDR1 polymorphisms and the pharmacokinetics of pravastatin. These results suggest that haplotypes are more informative in predicting the OATP-C phenotype than single SNPs...

..In this study the SLC10A2 gene was investigated to identify novel genetic variants and their association with gallstone formation...

..Here, we explore the capacity of antimalarial drugs to induce drug metabolism via activation of constitutive androstane receptors (CAR) by ligand binding...

..We here investigate whether they exert differential effects on the induction of these genes via activation of pregnane X receptor (PXR) and constitutive androstane receptor (CAR)...

..We suggest that ABCB1, but not CYP3A5, may predict short-term remission of Tac in steroid-refractory UC...

..We tested whether esomeprazole-induced healing of gastroesophageal reflux disease (GERD) is related to CYP2C19 genotype...

..Because the MDR1 single nucleotide polymorphism C3435T is associated with lower intestinal P-glycoprotein expression, we tested whether this polymorphism predisposes to development of ulcerative colitis...

..35; 95% CI, 1.34-4.14). Our functional and patient-based results suggest that the TC21 -582C>T polymorphism improves prediction of tamoxifen treatment outcome in breast cancer...

..38, 95% CI 1.03 to1.84, p = 0.02882). The newly identified genetic association of TCF-4 with ileal CD provides evidence that the decrease in Paneth cell alpha-defensins is a primary factor in disease pathogenesis...

..Measurement of rhodamine efflux using flow-cytometry from peripheral blood cells allows assessment of genetically determined differences in P-glycoprotein function...

..2, in comparison to 2D6.1, whereas only modest Km changes were observed. Taken together, these data provide further insight into the complex mechanisms that govern the highly variable expression and function of CYP2D6...

..In Caucasians the occurrence of these genetic variants appears to be extremely rare since none of these alleles were identified in a randomly selected control population of 1048 individuals...

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..Tamoxifen is a standard endocrine therapy for the prevention and treatment of steroid hormone receptor-positive breast cancer...

..The predictability of the new strategy was systematically evaluated. The semiautomatic TaqMan assay allows high sample throughput and will be useful for pharmacogenetic studies and in the clinical setting...

..In conclusion, MDR1 and other drug transporters represent plausible candidates as Parkinson's disease risk genes. Larger studies are required to confirm this role in the etiology of Parkinson's disease...

..In conclusion, thyroid abnormalities can exert significant effects on the expression of P-glycoprotein, thereby altering the disposition and action of drugs that are substrates of P-glycoprotein...

..The potential of UGT genotyping to identify patients who are at increased risk for failure of therapy and/or adverse effects of statins warrants further investigation...

..For other enzymes tested, carriers of reduced-function CYP2C9 (*2, *3) alleles had lower plasma concentrations of active metabolites (P < 0.004), pointing to the role of additional pathways...

..Their identification is clinically relevant but remains unsatisfactory because of incomplete characterization of the major allele involved, termed CYP2D6*41 (-1584C, R296C, S486T)...

..Taken together, the MDR1 polymorphisms C3435T and G2677T are associated with altered P-glycoprotein expression in the human placenta, and may have clinical consequences due to genetically determined, variable drug exposure of the fetus...

..17 (T26S, D28G, R29T) appeared to be functionally normal. These data extend the CYP2B6 knowledge base and should be particularly relevant for anti-HIV-therapy with efavirenz...

..We investigated genetic and nongenetic POR variability and its impact on drug-oxidation activities in human liver microsomes...

..No accumulation was observed when it was administered at intervals of 4 or 8 weeks. Methotrexate may reduce the clearance of infliximab from serum...

..Furthermore, our results indicate that TRF measurement in easily accessible tissues such as blood could serve as a surrogate parameter for the relative telomere length in other tissues...

..The method was successfully applied to the determination of pharmacokinetic parameters of esomeprazole and the two major metabolites after a single dose and under steady state conditions...

..This indicates consequences for hepatic elimination of and response to OCT substrates such as metformin...

..The method was used for investigating the stability of urine samples and the influence of urine collection at different times...

..To avoid severe hematotoxicity in patients, determination of the TPMT (thiopurine S-methyltransferase) genotype before commencing thiopurine therapy has become accepted...

..Taken together, these studies indicate that the formation of the active metabolite of nabumetone, 6-MNA, is predominantly catalyzed by CYP1A2 in HLMs with only minor contribution of other P450s...

..033). In conclusion, a lower HBD-2 gene copy number in the beta-defensin locus predisposes to colonic CD, most likely through diminished beta-defensin expression...

..These results establish the single nucleotide polymorphism 516G>Tasthe causal sequence variation for severely decreased expression and function associated with CYP2B6*6...

..This new link established between a human inflammatory bowel disease and the Wnt pathway/Tcf-4 provides a novel mechanism for pathogenesis in patients with ileal CD...

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..In this review, we summarize general biomolecular and pharmacological features and present a detailed up-to-date description of genetic polymorphisms, including a discussion of recent clinical applications of CYP2B6 pharmacogenetics...

..We investigated the predictive value of genetic variants of CYP2D6, CYP2C19, and three other cytochrome P450 enzymes for tamoxifen treatment outcome...

..Hepatobiliary elimination is a vectorial process involving uptake transporters in the basolateral hepatocyte membrane, possibly Phase I and Phase II metabolizing enzymes, and ATP-dependent efflux pumps in the apical hepatocyte membrane...

..Several nonsynonymous and promoter single-nucleotide polymorphisms (SNPs) in the CYP2B6 gene are associated with altered hepatic expression and function, which affect drug plasma concentrations...

..In this review, we provide an up-to-date summary of the functional polymorphisms and aspects of the functional genomics of the major human drug-metabolizing cytochrome P450s, as well as their clinical significance...

..0157). In future studies a single tag SNP selected of this haplotype block will provide reliable genetic testing to investigate systemically the influence of the SLC10A2 haplotype for disease susceptibility and/or drug response...

..The formation of active metabolites is catalyzed by the polymorphic cytochrome P450 2D6 (CYP2D6) enzyme...

..The adverse effects studied comprised effects related to the central nervous system, cardiovascular effects, and sexual dysfunction...

..Clinical studies on the effects of the C3435T polymorphism and drug treatment with cardiac glycosides, the immunosuppressants cyclosporine and tacrolimus, HIV protease inhibitors, and tricyclic antidepressants are discussed...

..Therefore initial genotyping for this enzyme and higher dosage in extensive metabolizers is likely to improve the clinical efficacy of proton pump inhibitors...

..These findings suggest that CYP3A5 may be a genetic determinant of interindividual differences in response to certain statins...

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..As several statins are P-glycoprotein substrates, beneficial as well as adverse effects of the statins might be affected by interindividual differences in P-glycoprotein expression or function caused by, e.g., the MDR1 polymorphism...

..Thus, the results of this study provide a solid basis to predict TPMT phenotype in a Northern European Caucasian population by molecular diagnostics...

..It can be assumed that for any novel therapeutic principle in IBD the approach of topical delivery will be also tried...

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..Variation in the expression of drug-metabolising enzymes and transport proteins affects the pharmacology of antimalarial drugs. Exploration of pharmacogenetics might help to optimise the use of antimalarial drugs...

..The aim of this study was to address the presently controversial question of whether cytochrome P450 (CYP) 3A5 polymorphism is associated with hypertension...

..This possibility should be taken into consideration if the diuretic and AZA or 6-mercaptopurine are coadministered. However, the extrapolation to the clinical setting remains open...

..The aim was to investigate whether polymorphisms in the SLCO1B1 gene, encoding the hepatic uptake transporter OATP1B1, influence the short-term effects of pravastatin on cholesterol synthesis...

..Paneth cells also express NOD2. To address the hypothesis that the function of NOD2 may affect expression of Paneth cell defensins, we compared their expression levels with respect to NOD2 mutations in Crohn's disease...

..These results suggest the possibility of drug interactions between thienopyridine derivates and drug substrates of CYP2B6 and CYP2C19...

..Therefore, we tested the hypothesis of a relationship between event-free survival and genotype distributions of seven polymorphic DNA repair enzymes and four cell cycle regulators...

..John's wort was found. In conclusion, sex, in addition to PXR and drug exposure, is a major factor for CYP3A4 expression in humans, thus explaining many of the previous observations of sex-dependent drug clearance...

..46, P < 0.0001) but did not depend on CYP2D6 genotype. These data demonstrate genotype-dependent mRNA expression for CYP2D6 and they emphasize the necessity of differentiating between the functional CYP2D6 and the CYP2D pseudogenes...

..These data indicate that other mechanisms including uptake transporter function are likely to play a role in fexofenadine disposition...

..No prominent changes in lung physiology parameters were observed following inhalation, suggesting good local tolerability of OMR-nanoplex formulation...

..The initial decrease in telomere restriction fragment could be caused by ontogeny-related functional alterations of hematopoietic cells or differences in stem cell turnover or the rate of telomere loss per cell division...

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..However, the therapeutic impact should be proved by clinical studies...

..The direct use of 6-thioguanine may offer a more rapid and safer alternative. We conducted an open prospective study to investigate the efficacy and safety of 6-thioguanine in chronic active Crohn's disease...

..Furthermore, a detailed interspecies comparison of CYP2B promoters and transcriptional start sites provided novel insights into evolutionary relationships...

..CONCLUSIONS: (S)-verapamil was about 20 times more potent than (R)-verapamil with regard to negative dromotropic effects on AV node conduction. (R)-verapamil but not (S)-verapamil significantly reduced the MAP as compared with placebo...

..To improve response rates in thiopurine therapy of IBD, comprehensive analyses including metabolic patterns and genome-wide profiling in patients with azathioprine/mercaptopurine treatment are required to identify novel candidate genes...

..18; 95% confidence interval, 1.44-18.62). We provide evidence that the TGFB2 -246ins polymorphism leads to enhanced TGF-beta(2) expression levels in vivo and might thereby contribute to tumor progression and development of metastases...

..In addition, because standard laboratory inflammatory parameters are poorly correlated with disease activity in IBD, the relation between PCT levels and disease activity was investigated...

..These findings contribute to better understanding of drug interactions with thioTEPA...

..These data demonstrate that the extensive interindividual variability of CYP2B6 expression and function is not only due to regulatory phenomena, but also caused by a common genetic polymorphism...

..032; OR 4.31, 95% CI 1.19-15.58) more frequent in diabetic patients (7.2 %) than in healthy volunteers from Romania (1.8%). The observations support the view that SGK-1 may participate in the pathogenesis of metabolic syndrome...

..Conspicuously, inflammation is associated with an enhanced goblet cell differentiation in CD but not in UC, a defect possibly of pathogenic importance...

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..The question whether interindividual variability of NDPK activity may explain differences in 6-thioguanosine 5'-phosphates levels has to be investigated in a prospective large-scale study...

..This article reviews the current knowledge of clinical resistance to small molecule inhibitors approved for treatment of cancer patients...

..4. In a well-standardized clinical setting of inflammatory bowel disease, neither mesalazine nor azathioprine significantly affected TPMT activity during a whole year of treatment...

..Thiopurine methyltransferase (TPMT) is involved in the metabolism of mercaptopurine and subject to genetic polymorphism, with heterozygous individuals having intermediate and homozygous mutant individuals having very low TPMT activity...

..4; 95% confidence interval, 1.2 to 148; P = 0.034). A dominant role of the donor's ABCB1 genotype was identified for development of CsA nephrotoxicity. This suggests that P-glycoprotein is an important factor in CsA nephrotoxicity...

..However, regarding phenprocoumon hydroxylation CYP2C9 genotypes had only marginal effects on S- and R-phenprocoumon total clearance in healthy volunteers...

..6% in a Caucasian study population. These data provide further insight into the genetic variability of CYP2B6 and demonstrate the existence of phenotypic null alleles in this gene...

..Therefore, MRP5-mediated cellular export may represent a novel, disease-dependent pathway for cGMP removal from cardiac cells...

..These results suggested a modulating role for host genetic variation in the development of CNS relapse in childhood ALL treated according to Berlin-Frankfurt-Münster protocols...

..An individual's response to MTX may in part be genetically determined by functional genetic variation in genes encoding these enzymes. We report a pharmacogenetic evaluation of MTX therapy in IBD...

..Thus, the specific deficiency of PC defensins that characterizes ileal CD may compromise innate immune defenses of the ileal mucosa and initiate and/or perpetuate this disease...

..The aim of the study was to explore systematically the association between NOD2/CARD15 variants and clinical response of perianal fistulas in patients using antibiotic therapy...