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

Maria Alice V Willrich, Alice C. Rodrigues, Alvaro Cerda, Fabiana D V Genvigir, Simone S. Arazi, Egidio L. Dorea, Marcia M S Bernik, Marcelo C. Bertolami, Andre Faludi, Alvaro Largura, Linnea M. Baudhuin, Sandra C. Bryant, Mario Hiroyuki Hirata, Rosario Dominguez Crespo Hirata

Research output: Contribution to journalArticle

16 Citations (Scopus)

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 (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.

Original languageEnglish (US)
Pages (from-to)157-163
Number of pages7
JournalClinica Chimica Acta
Volume421
DOIs
StatePublished - Jun 5 2013

Fingerprint

Cytochrome P-450 CYP3A
Messenger RNA
Atorvastatin Calcium
Haplotypes
Hydroxymethylglutaryl-CoA Reductase Inhibitors
Blood Cells
Blood
Hypercholesterolemia
Hydrocortisone

Keywords

  • Atorvastatin
  • CYP3A activity
  • CYP3A4
  • CYP3A5
  • MRNA expression
  • Pharmacogenomics

ASJC Scopus subject areas

  • Biochemistry
  • Clinical Biochemistry
  • Biochemistry, medical

Cite this

Willrich, M. A. V., Rodrigues, A. C., Cerda, A., Genvigir, F. D. V., Arazi, S. S., Dorea, E. L., ... Hirata, R. D. C. (2013). Effects of atorvastatin on CYP3A4 and CYP3A5 mRNA expression in mononuclear cells and CYP3A activity in hypercholeresterolemic patients. Clinica Chimica Acta, 421, 157-163. https://doi.org/10.1016/j.cca.2013.03.007

Effects of atorvastatin on CYP3A4 and CYP3A5 mRNA expression in mononuclear cells and CYP3A activity in hypercholeresterolemic patients. / Willrich, Maria Alice V; Rodrigues, Alice C.; Cerda, Alvaro; Genvigir, Fabiana D V; Arazi, Simone S.; Dorea, Egidio L.; Bernik, Marcia M S; Bertolami, Marcelo C.; Faludi, Andre; Largura, Alvaro; Baudhuin, Linnea M.; Bryant, Sandra C.; Hirata, Mario Hiroyuki; Hirata, Rosario Dominguez Crespo.

In: Clinica Chimica Acta, Vol. 421, 05.06.2013, p. 157-163.

Research output: Contribution to journalArticle

Willrich, MAV, Rodrigues, AC, Cerda, A, Genvigir, FDV, Arazi, SS, Dorea, EL, Bernik, MMS, Bertolami, MC, Faludi, A, Largura, A, Baudhuin, LM, Bryant, SC, Hirata, MH & Hirata, RDC 2013, 'Effects of atorvastatin on CYP3A4 and CYP3A5 mRNA expression in mononuclear cells and CYP3A activity in hypercholeresterolemic patients', Clinica Chimica Acta, vol. 421, pp. 157-163. https://doi.org/10.1016/j.cca.2013.03.007
Willrich, Maria Alice V ; Rodrigues, Alice C. ; Cerda, Alvaro ; Genvigir, Fabiana D V ; Arazi, Simone S. ; Dorea, Egidio L. ; Bernik, Marcia M S ; Bertolami, Marcelo C. ; Faludi, Andre ; Largura, Alvaro ; Baudhuin, Linnea M. ; Bryant, Sandra C. ; Hirata, Mario Hiroyuki ; Hirata, Rosario Dominguez Crespo. / Effects of atorvastatin on CYP3A4 and CYP3A5 mRNA expression in mononuclear cells and CYP3A activity in hypercholeresterolemic patients. In: Clinica Chimica Acta. 2013 ; Vol. 421. pp. 157-163.
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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

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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