title: The effect of atorvastatin treatment on serum oxysterol concentrations and cytochrome P450 3A4 activity.
abstract: OBJECTIVE
  Atorvastatin is known to both inhibit and induce the cytochrome P450 3A4 (CYP3A4) enzyme in vitro. Some clinical studies indicate that atorvastatin inhibits CYP3A4 but there are no well-controlled longer term studies that could evaluate the inducing effect of atorvastatin. We aimed to determine if atorvastatin induces or inhibits CYP3A4 activity as measured by the 4β-hydroxycholesterol to cholesterol ratio (4βHC : C).
  
  
  METHODS
  In this randomized, double-blind, placebo-controlled 6 month study we evaluated the effects of atorvastatin 20 mg day(-1) (n = 15) and placebo (n = 14) on oxysterol concentrations and determined if atorvastatin induces or inhibits CYP3A4 activity as assessed by the 4βHC : C index. The respective 25-hydroxycholesterol and 5α,6α-epoxycholesterol ratios were used as negative controls.
  
  
  RESULTS
  Treatment with atorvastatin decreased 4βHC and 5α,6α-epoxycholesterol concentrations by 40% and 23%, respectively. The mean 4βHC : C ratio decreased by 13% (0.214 ± 0.04 to 0.182 ± 0.04, P = 0.024, 95% confidence interval (CI) of the difference -0.0595, -0.00483) in the atorvastatin group while no significant change occurred in the placebo group. The difference in change of 4βHC : C between study arms was statistically significant (atorvastatin -0.032, placebo 0.0055, P = 0.020, 95% CI of the difference -0.069, -0.0067). The ratios of 25-hydroxycholesterol and 5α,6α-epoxycholesterol to cholesterol did not change.
  
  
  CONCLUSIONS
  The results establish atorvastatin as an inhibitor of CYP3A4 activity. Furthermore, 4βHC : C is a useful index of CYP3A4 activity, including the conditions with altered cholesterol concentrations.
authors.affiliation: Research Center for Internal Medicine, University of Oulu, Oulu.|Department of Internal Medicine, Oulu University Hospital, Oulu.|Biocenter Oulu, Oulu.|Medical Research Center Oulu, Oulu University Hospital and University of Oulu, Oulo.
authors.forename: Janne
authors.identifier: http://orcid.org/0000-0003-4981-0525
authors.initials: J
authors.lastname: Hukkanen
authors.affiliation: Medical Research Center Oulu, Oulu University Hospital and University of Oulu, Oulo.|Department of Obstetrics and Gynaecology, Institute of Clinical Medicine, University of Oulu, Oulu.|Department of Obstetrics and Gynaecology, Oulu University Hospital, Oulo, Finland.
authors.forename: Johanna
authors.initials: J
authors.lastname: Puurunen
authors.affiliation: Steno Diabetes Center, Gentofte, Denmark.
authors.forename: Tuulia
authors.initials: T
authors.lastname: Hyötyläinen
authors.affiliation: Research Center for Internal Medicine, University of Oulu, Oulu.|Department of Internal Medicine, Oulu University Hospital, Oulu.|Biocenter Oulu, Oulu.|Medical Research Center Oulu, Oulu University Hospital and University of Oulu, Oulo.
authors.forename: Markku J
authors.initials: MJ
authors.lastname: Savolainen
authors.affiliation: Department of Clinical Chemistry, Institute of Diagnostics, University of Oulu, Oulu.|NordLab Oulu, Oulu University Hospital, Oulu.
authors.forename: Aimo
authors.initials: A
authors.lastname: Ruokonen
authors.affiliation: Medical Research Center Oulu, Oulu University Hospital and University of Oulu, Oulo.|Department of Obstetrics and Gynaecology, Institute of Clinical Medicine, University of Oulu, Oulu.|Department of Obstetrics and Gynaecology, Oulu University Hospital, Oulo, Finland.
authors.forename: Laure
authors.initials: L
authors.lastname: Morin-Papunen
authors.affiliation: Steno Diabetes Center, Gentofte, Denmark.
authors.forename: Matej
authors.initials: M
authors.lastname: Orešič
authors.affiliation: Medical Research Center Oulu, Oulu University Hospital and University of Oulu, Oulo.|Department of Obstetrics and Gynaecology, Institute of Clinical Medicine, University of Oulu, Oulu.|Department of Obstetrics and Gynaecology, Oulu University Hospital, Oulo, Finland.
authors.forename: Terhi
authors.initials: T
authors.lastname: Piltonen
authors.affiliation: Medical Research Center Oulu, Oulu University Hospital and University of Oulu, Oulo.|Department of Obstetrics and Gynaecology, Institute of Clinical Medicine, University of Oulu, Oulu.|Department of Obstetrics and Gynaecology, Oulu University Hospital, Oulo, Finland.|Department of Obstetrics and Gynaecology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.
authors.forename: Juha S
authors.initials: JS
authors.lastname: Tapanainen
mesh_terms: D000328:Adult; D000069059:Atorvastatin / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D002784:Cholesterol / Q000031:analogs & derivatives* / Q000097:blood; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism*; D065692:Cytochrome P-450 CYP3A Inhibitors / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D006888:Hydroxycholesterols / Q000097:blood*; D008875:Middle Aged; D011085:Polycystic Ovary Syndrome / Q000097:blood / Q000201:enzymology
chemical_list: C119784:5,6-epoxycholesterol; D065692:Cytochrome P-450 CYP3A Inhibitors; D006888:Hydroxycholesterols; C099828:cholest-5-ene-3,4-diol; D002784:Cholesterol; D000069059:Atorvastatin; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human
keywords: 25-hydroxycholesterol; 4β-hydroxycholesterol; 5α,6α-epoxycholesterol; atorvastatin; desmosterol; pregnane X receptor