title: Effects of atorvastatin on CYP3A4 and CYP3A5 mRNA expression in mononuclear cells and CYP3A activity in hypercholeresterolemic patients.
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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Clinical and Toxicological Analyses, School of Pharmaceutical Sciences, University of Sao Paulo, Sao Paulo, SP, Brazil. malicewi@usp.br
authors.forename: Maria Alice V
authors.initials: MA
authors.lastname: Willrich
authors.forename: Alice C
authors.initials: AC
authors.lastname: Rodrigues
authors.forename: Alvaro
authors.initials: A
authors.lastname: Cerda
authors.forename: Fabiana D V
authors.initials: FD
authors.lastname: Genvigir
authors.forename: Simone S
authors.initials: SS
authors.lastname: Arazi
authors.forename: Egidio L
authors.initials: EL
authors.lastname: Dorea
authors.forename: Marcia M S
authors.initials: MM
authors.lastname: Bernik
authors.forename: Marcelo C
authors.initials: MC
authors.lastname: Bertolami
authors.forename: Andre
authors.initials: A
authors.lastname: Faludi
authors.forename: Alvaro
authors.initials: A
authors.lastname: Largura
authors.forename: Linnea M
authors.initials: LM
authors.lastname: Baudhuin
authors.forename: Sandra C
authors.initials: SC
authors.lastname: Bryant
authors.forename: Mario Hiroyuki
authors.initials: MH
authors.lastname: Hirata
authors.forename: Rosario Dominguez Crespo
authors.initials: RD
authors.lastname: Hirata
mesh_terms: D000328:Adult; D000368:Aged; D000924:Anticholesteremic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D000069059:Atorvastatin; D016022:Case-Control Studies; D008078:Cholesterol, LDL / Q000378:metabolism; D051544:Cytochrome P-450 CYP3A / Q000235:genetics / Q000378:metabolism*; D004334:Drug Administration Schedule; D005260:Female; D015870:Gene Expression / Q000187:drug effects*; D018740:Genetic Heterogeneity; D006239:Haplotypes; D006538:Heptanoic Acids / Q000494:pharmacology* / Q000627:therapeutic use; D006801:Humans; D006937:Hypercholesterolemia / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D007963:Leukocytes, Mononuclear / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008297:Male; D008875:Middle Aged; D010641:Phenotype; D011758:Pyrroles / Q000494:pharmacology* / Q000627:therapeutic use; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism
chemical_list: D000924:Anticholesteremic Agents; D008078:Cholesterol, LDL; D006538:Heptanoic Acids; D011758:Pyrroles; D012333:RNA, Messenger; D000069059:Atorvastatin; C510164:CYP3A5 protein, human; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human