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Eur J Clin Pharmacol. 2001 Mar;56(12):881-8.

Cytochrome P450 isoforms involved in melatonin metabolism in human liver microsomes.

Author information

1
Department of Medical Laboratory Sciences and Technology, Division of Clinical Pharmacology, Huddinge University Hospital, Karolinska Institutet, 14186 Stockholm, Sweden.

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 microM. 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 microM and 10 microM, respectively, after incubation with 50 microM 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.

PMID:
11317475
DOI:
10.1007/s002280000245
[Indexed for MEDLINE]

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