TY - JOUR
T1 - Effects of atorvastatin on CYP3A4 and CYP3A5 mRNA expression in mononuclear cells and CYP3A activity in hypercholeresterolemic patients
AU - Willrich, Maria Alice V.
AU - Rodrigues, Alice C.
AU - Cerda, Alvaro
AU - Genvigir, Fabiana D.V.
AU - Arazi, Simone S.
AU - Dorea, Egidio L.
AU - Bernik, Marcia M.S.
AU - Bertolami, Marcelo C.
AU - Faludi, Andre
AU - Largura, Alvaro
AU - Baudhuin, Linnea M.
AU - Bryant, Sandra C.
AU - Hirata, Mario Hiroyuki
AU - Hirata, Rosario Dominguez Crespo
N1 - Funding Information:
This study was supported by grants from CNPq (# 502171/2004-9 ), Brasilia, and FAPESP (# 2008/06667-9 ), Sao Paulo, Brazil. M. A. V. Willrich, A. C. Rodrigues and F. D. V. Genvigir were recipients of scholarships from FAPESP. A. Cerda is the recipient of a fellowship from CONYCIT, Chile . M.H. Hirata and R.D.C. Hirata are recipients of fellowships from CNPq. This publication statistical analysis was supported by NIH/NCRR CTSA Grant Number UL1 RR024150 . Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the NIH.
PY - 2013/6/5
Y1 - 2013/6/5
N2 - 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 (R2=0.039, p=0.037) and CYP3A5 (R2=0.047, p=0.019) mRNA levels and negatively correlated with CYP3A activity (R2=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 atorvastatin 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.
AB - 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 (R2=0.039, p=0.037) and CYP3A5 (R2=0.047, p=0.019) mRNA levels and negatively correlated with CYP3A activity (R2=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 atorvastatin 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.
KW - Atorvastatin
KW - CYP3A activity
KW - CYP3A4
KW - CYP3A5
KW - MRNA expression
KW - Pharmacogenomics
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U2 - 10.1016/j.cca.2013.03.007
DO - 10.1016/j.cca.2013.03.007
M3 - Article
C2 - 23501331
AN - SCOPUS:84876331758
SN - 0009-8981
VL - 421
SP - 157
EP - 163
JO - Clinica Chimica Acta
JF - Clinica Chimica Acta
ER -