Intronic polymorphism in CYP3A4 affects hepatic expression and response to statin drugs.
TLDR
The results indicate that intron 6 SNP rs35599367 markedly affects expression of CYP3A4 and could serve as a biomarker for predicting response to CYP2A4-metabolized drugs.Abstract:
Cytochrome P450 3A4 (CYP3A4) metabolizes ∼50% of all clinically used drugs. Although CYP3A4 expression varies widely between individuals, the contribution of genetic factors remains uncertain. In this study, we measured allelic CYP3A4 heteronuclear RNA (hnRNA) and mRNA expression in 76 human liver samples heterozygous for at least one of eight marker SNPs and found marked allelic expression imbalance (1.6–6.3-fold) in 10/76 liver samples (13%). This was fully accounted for by an intron 6 SNP (rs35599367, C>T), which also affected mRNA expression in cell culture on minigene transfections. CYP3A4 mRNA level and enzyme activity in livers with CC genotype were 1.7- and 2.5-fold, respectively, greater than in CT and TT carriers. In 235 patients taking stable doses of atorvastatin, simvastatin, or lovastatin for lipid control, carriers of the T allele required significantly lower statin doses (0.2–0.6-fold, P=0.019) than non-T carriers for optimal lipid control. These results indicate that intron 6 SNP rs35599367 markedly affects expression of CYP3A4 and could serve as a biomarker for predicting response to CYP3A4-metabolized drugs.read more
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Cytochrome P450 enzymes in drug metabolism: Regulation of gene expression, enzyme activities, and impact of genetic variation
TL;DR: Recent progress on drug metabolism activity profiles, interindividual variability and regulation of expression, and the functional and clinical impact of genetic variation in drug metabolizing P450s are reviewed.
Journal ArticleDOI
SLCO1B1 polymorphism markedly affects the pharmacokinetics of simvastatin acid.
TL;DR: The SLCO1B1*1B/*1B*5/*15 and *15/*15 genotypes markedly increase the exposure to active lovastatin acid, but have no significant effect on Lovastatin lactone, similar to their effects on simvastatin and simvASTatin acid.
Journal ArticleDOI
Therapeutic Drug Monitoring of Tacrolimus-Personalized Therapy : Second Consensus Report
Mercè Brunet,Teun van Gelder,Anders Åsberg,Vincent Haufroid,Vincent Haufroid,Dennis A. Hesselink,Loralie J. Langman,Florian Lemaitre,Pierre Marquet,Christoph Seger,Maria Shipkova,Alexander A. Vinks,Alexander A. Vinks,Pierre Wallemacq,Eberhard Wieland,Jean-Baptiste Woillard,Markus J. Barten,Klemens Budde,Helena Colom,Maja Theresa Dieterlen,Laure Elens,Kamisha L. Johnson-Davis,Paweł K. Kunicki,Iain MacPhee,Satohiro Masuda,Binu S. Mathew,Olga Millán,Tomoyuki Mizuno,Tomoyuki Mizuno,Dirk Jan A.R. Moes,Caroline Monchaud,Ofelia Noceti,Tomasz Pawinski,Nicolas Picard,Ron H.N. van Schaik,Claudia Sommerer,Nils Tore Vethe,Brenda C. M. de Winter,Uwe Christians,Stein Bergan +39 more
TL;DR: It is concluded that considerable advances in the different fields of tacrolimus monitoring have been achieved during this last decade, and the Expert Committee concludes that Continued efforts should focus on the opportunities to implement in clinical routine the combination of new standardized PK approaches with PG, and valid biomarkers to further personalize tacolimus therapy and to improve long-term outcomes for treated patients.
Journal ArticleDOI
The contributions of oxytocin and vasopressin pathway genes to human behavior.
TL;DR: Evidence is discussed from a variety of research tracks including molecular genetics, imaging genomics, pharmacology and endocrinology that support the conclusions drawn from association studies of social phenotypes and detail how common polymorphisms in AVP-OXT pathway genes contribute to the behavioral hard wiring that enables individual Homo sapiens to interact successfully with conspecifics.
Journal ArticleDOI
A New Functional CYP3A4 Intron 6 Polymorphism Significantly Affects Tacrolimus Pharmacokinetics in Kidney Transplant Recipients
Laure Elens,Rachida Bouamar,Dennis A. Hesselink,Vincent Haufroid,Ilse P. van der Heiden,Teun van Gelder,Ron H.N. van Schaik +6 more
TL;DR: The CYP3A4 rs35599367C>T polymorphism is associated with a significantly altered Tac metabolism and therefore increases the risk of supratherapeutic Tac concentrations early after transplantation.
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