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(Reference retrieved automatically from Web of Science through information on FAPESP grant and its corresponding number as mentioned in the publication by the authors.)

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

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Author(s):
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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]
Total Authors: 14
Affiliation:
[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
Total Affiliations: 6
Document type: Journal article
Source: Clinica Chimica Acta; v. 421, p. 157-163, JUN 5 2013.
Web of Science Citations: 14
Abstract

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)

FAPESP's process: 08/06667-9 - Association study of 230 polymorphisms in 60 candidate genes and response to atorvastatin
Grantee:Rosario Dominguez Crespo Hirata
Support type: Regular Research Grants