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 Scopus citations

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

Keywords

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

ASJC Scopus subject areas

  • Biochemistry
  • Clinical Biochemistry
  • Biochemistry, medical

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    Willrich, M. A. V., Rodrigues, A. C., Cerda, A., Genvigir, F. D. V., Arazi, S. S., Dorea, E. L., Bernik, M. M. S., Bertolami, M. C., Faludi, A., Largura, A., Baudhuin, L. M., Bryant, S. C., Hirata, M. H., & 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