Effects of atorvastatin on CYP3A4 and CYP3A5 mRNA ... - BV FAPESP
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Effects of atorvastatin on CYP3A4 and CYP3A5 mRNA expression in mononuclear cells and CYP3A activity in hypercholeresterolemic patients

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Autor(es):
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Willrich, Maria Alice V. [1] ; Rodrigues, Alice C. [1] ; Cerda, Alvaro [1] ; Genvigir, Fabiana D. V. [1] ; Arazi, Simone S. [1] ; Dorea, Egidio L. [2] ; Bernik, Marcia M. S. [2] ; Bertolami, Marcelo C. [3] ; Faludi, Andre [3] ; Largura, Alvaro [4] ; Baudhuin, Linnea M. [5] ; Bryant, Sandra C. [6] ; Hirata, Mario Hiroyuki [1] ; Crespo Hirata, Rosario Dominguez [1]
Número total de Autores: 14
Afiliação do(s) autor(es):
[1] Univ Sao Paulo, Sch Pharmaceut Sci, Dept Clin & Toxicol Anal, BR-05508900 Sao Paulo - Brazil
[2] Univ Sao Paulo, Univ Hosp, BR-05508900 Sao Paulo - Brazil
[3] Dante Pazzanezze Inst Cardiol, Sao Paulo - Brazil
[4] Paranalise Lab, Curitiba, PR - Brazil
[5] Mayo Clin, Dept Lab Med & Pathol, Rochester, MN - USA
[6] Mayo Clin, Div Biomed Stat & Informat, Rochester, MN - USA
Número total de Afiliações: 6
Tipo de documento: Artigo Científico
Fonte: Clinica Chimica Acta; v. 421, p. 157-163, JUN 5 2013.
Citações Web of Science: 14
Resumo

Background: Variability of response to statins has been related to polymorphisms in genes involved in cholesterol homeostasis and statin metabolism, such as CYP3A4 and CYP3A5. We investigated the effects of atorvastatin on CYP3A4 and CYP3A5 mRNA expression in mononuclear cells and on CYP3A activity and their interactions with common variants. Methods: Unrelated individuals (n = 121) with hypercholesterolemia (HC) were treated with atorvastatin (10 mg/day/4 weeks). Ninety-two normolipidemic (NL) subjects were selected as a control group. Genotype analysis of CYP3A4{*}1B (rs2740574), CYP3A4{*}22 (rs35599367), CYP3A5{*}3C (rs776746), and CYP3A5{*}1D (rs15524) and mRNA levels in peripheral blood mononuclear cells (PBMCs) were estimated. CYP3A activity was phenotyped by the urinary cortisol to 6-beta-hydroxy-cortisol ratio. Results: LDL cholesterol reduction in response to atorvastatin was positively correlated with change in CYP3A4 (R-2 = 0.039, p = 0.037) and CYP3A5 (R-2 = 0.047, p = 0.019) mRNA levels and negatively correlated with CYP3A activity (R-2 = 0.071, p = 0.022). CYP3A5{*}3C (AGT haplotype) was associated to lower basal CYP3A5 mRNA expression in HC (p < 0.045), however none of the haplotype groups impacted treatment. Conclusion: It is likely that cholesterolemia status changes promoted by atonrastatin play a role in regulating CYP3A4 and CYP3A5 mRNA expression in PBMCs, as well as CYP3A activity. CYP3A5{*}3C (AGT haplotype) also contributes for the variability of CYP3A5 mRNA levels in PBMCs. (C) 2013 Elsevier B.V. All rights reserved. (AU)

Processo FAPESP: 08/06667-9 - Estudo de associação entre 230 polimorfismos em 60 genes candidatos e a resposta a atorvastatina
Beneficiário:Rosario Dominguez Crespo Hirata
Modalidade de apoio: Auxílio à Pesquisa - Regular