European Journal of Clinical Pharmacology

, Volume 56, Issue 12, pp 881–888

Cytochrome P450 isoforms involved in melatonin metabolism in human liver microsomes

  • Gabriella Facciolá
  • Mats Hidestrand
  • Christer von Bahr
  • Gunnel Tybring
Pharmacokinetics and Disposition

DOI: 10.1007/s002280000245

Cite this article as:
Facciolá, G., Hidestrand, M., von Bahr, C. et al. Eur J Clin Pharmacol (2001) 56: 881. doi:10.1007/s002280000245

Abstract

Objective: The present study was carried out to identify the cytochrome P450 enzyme(s) involved in the 6-hydroxylation and O-demethylation of melatonin. Methods: The formation kinetics of 6-hydroxymelatonin and N-acetylserotonin were determined using human liver microsomes and cDNA yeast-expressed human enzymes (CYP1A2, 2C9 and 2C19) over the substrate concentration range 1–1000 µM. Selective inhibitors and substrates of various cytochrome P450 enzymes were also employed. Results: Fluvoxamine was a potent inhibitor of 6-hydroxymelatonin formation, giving 50±5% and 69±9% inhibition at concentrations of 1 µM and 10 µM, respectively, after incubation with 50 µM melatonin. Furafylline, sulphaphenazole and omeprazole used at low and high concentrations substantially inhibited both metabolic pathways. cDNA yeast-expressed CYP1A2, CYP2C9 and CYP2C19 catalysed the formation of the two metabolites, confirming the data obtained with specific inhibitors and substrates. Conclusions: Our results strongly suggest that 6-hydroxylation, the main metabolic pathway of melatonin, is mediated mainly, but not exclusively, by CYP1A2, the high-affinity enzyme involved in melatonin metabolism, confirming the observation that a single oral dose of fluvoxamine increases nocturnal serum melatonin levels in healthy subjects. Furthermore, the results indicate that there is a potential for interaction with drugs metabolised by CYP1A2 both at physiological levels and after oral administration of melatonin, while CYP2C19 and CYP2C9 are assumed to be less important.

Cytochrome P450 Melatonin metabolism CYP1A2

Copyright information

© Springer-Verlag 2001

Authors and Affiliations

  • Gabriella Facciolá
    • 1
  • Mats Hidestrand
    • 2
  • Christer von Bahr
    • 3
  • Gunnel Tybring
    • 1
  1. 1.Department of Medical Laboratory Sciences and Technology, Division of Clinical Pharmacology, Huddinge University Hospital, Karolinska Institutet, 14186 Stockholm, SwedenSweden
  2. 2.National Institute of Environmental Medicine, Division of Molecular Toxicology, Karolinska Institutet, 171 77 Stockholm, SwedenSweden
  3. 3.Department of Medicine, Division of Clinical Pharmacology, Stockholm Söder Hospital, 11883 Stockholm, SwedenSweden