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

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Abstract

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.

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Acknowledgments

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.

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Authors and Affiliations

  1. Center for Psychopharmacology, Diakonhjemmet Hospital, PO Box 85, Vinderen, N-0319, Oslo, Norway

    Caroline Gjestad, Kristine Hole, Tore Haslemo & Espen Molden

  2. Department of Laboratory Medicine, Karolinska Institutet, Huddinge, Sweden

    Ulf Diczfalusy

  3. Department of Pharmaceutical Biosciences, School of Pharmacy, University of Oslo, Oslo, Norway

    Espen Molden

Authors
  1. Caroline Gjestad
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  2. Kristine Hole
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  4. Ulf Diczfalusy
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  5. Espen Molden
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Correspondence to Caroline Gjestad.

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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.

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Gjestad, C., Hole, K., Haslemo, T. et al. Effect of Grapefruit Juice Intake on Serum Level of the Endogenous CYP3A4 Metabolite 4β-Hydroxycholesterol—an Interaction Study in Healthy Volunteers. AAPS J 21, 58 (2019). https://doi.org/10.1208/s12248-019-0330-1

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