The AAPS Journal

, 21:58 | Cite as

Effect of Grapefruit Juice Intake on Serum Level of the Endogenous CYP3A4 Metabolite 4β-Hydroxycholesterol—an Interaction Study in Healthy Volunteers

  • Caroline GjestadEmail author
  • Kristine Hole
  • Tore Haslemo
  • Ulf Diczfalusy
  • Espen Molden
Research Article


4β-Hydroxycholesterol (4βOHC) is an endogenous CYP3A4 metabolite. However, it is unclear whether circulating levels of 4βOHC may reflect hepatic CYP3A4 activity or both hepatic and intestinal enzyme activity. The aim of this study was to investigate the effect of grapefruit juice, regarded to be a selective intestinal CYP3A4 inhibitor, on serum 4βOHC levels in healthy volunteers. The participants (n = 22) consumed grapefruit juice twice daily for 3 weeks followed by a 2-week washout period. Blood samples for measurements of 4βOHC and the non-CYP3A4-derived oxysterols 24-hydroxycholesterol (24OHC) and 27-hydroxycholesterol (27OHC), as well as lathosterol and total cholesterol, were drawn on days 0, 7, 21, and 35. Median individual changes (ratios) in cholesterol-corrected 4βOHC levels from baseline to weeks 1, 3, and 5 were 0.94 (P = 0.2), 0.98 (P = 0.3), and 0.97 (P = 0.9), respectively. In comparison, median changes (ratios) in cholesterol-corrected levels of 24OHC at the same points were 1.01 (P = 0.6), 0.98 (P = 0.3), and 0.99 (P = 0.5), and of 27OHC 1.01 (P = 0.8), 0.97 (P = 0.5), and 0.99 (P = 0.2). Surprisingly, serum concentration of cholesterol was significantly reduced by approximately 5% after 1 week (P = 0.03), while median cholesterol-corrected levels of lathosterol increased significantly and persistently by approximately 15% during the whole 5-week period (P < 0.04). In conclusion, the present findings suggest that intestinal CYP3A4 is not relevant for the overall formation of 4βOHC in healthy volunteers. The fact that grapefruit juice altered cholesterol homeostasis should be further investigated.


4β-hydroxycholesterol oxysterols CYP3A4 grapefruit juice 



We acknowledge the South-Eastern Norway Regional Health Authority for PhD funding to author C. G. Moreover, we are grateful to the Department of Medical Biochemistry at Diakonhjemmet Hospital for performing measurements of cholesterol.

Compliance with Ethical Standards

The study was approved by the Regional Committee for Medical and Health Research Ethics and the Hospital’s Research Committee, and written informed consent was obtained from all participants.

Supplementary material

12248_2019_330_MOESM1_ESM.docx (15 kb)
ESM 1 (DOCX 15 kb)


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Copyright information

© American Association of Pharmaceutical Scientists 2019

Authors and Affiliations

  • Caroline Gjestad
    • 1
    Email author
  • Kristine Hole
    • 1
  • Tore Haslemo
    • 1
  • Ulf Diczfalusy
    • 2
  • Espen Molden
    • 1
    • 3
  1. 1.Center for PsychopharmacologyDiakonhjemmet HospitalOsloNorway
  2. 2.Department of Laboratory MedicineKarolinska InstitutetHuddingeSweden
  3. 3.Department of Pharmaceutical Biosciences, School of PharmacyUniversity of OsloOsloNorway

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