Cytochrome P 450 isoforms involved in melatonin metabolism in human liver microsomes
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.
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The majority of melatonin is metabolized through CYP1A2, with lesser metabolic activity through CYP1A1, CYP1B1, and CYP2C19.
“Earlier research has identified that the majority of melatonin is metabolized through cytochrome (CYP) 1A2 [292,301], with lesser metabolic activity through CYP1A1, CYP1B1, and CYP2C19 [292,302].”
From Is Melatonin the “Next Vitamin D”?: A Review of Emerging Science, Clinical Uses, Safety, and Dietary Supplements (2022) · cites this paper as [301]
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Abass, K. M. (2010) · Cited by 10 · see citing works
Wang, X., Yang, F., Zhang, J.-C., et al. (2023) · Plant Cell Reports · doi:10.1007/s00299-022-02969-5 · Cited by 9 · see citing works
Adeyemi, W. J., Abdussalam, T. A., Abdulrahim, H. A., et al. (2020) · Toxicology and Industrial Health · doi:10.1177/0748233720937199 · Cited by 9 · see citing works
“The main pathway for the metabolism of the hormone in the hepatic tissue is through hydroxylation at the C-6 position by 6-hydroxylase and P450 cytochromes (Facciolá et al., 2001), resulting in the synthesis of 6-hydroxymelatonin, which is conjugated with glucuronide and sulfate to 6-hydroxymelatonin glucuronide or su…”
MethodConstruction of a fused grid-based CYP2C19-Template system and the application
Yamamura, Y., Yoshinari, K., & Yamazoe, Y. (2022) · Drug Metabolism and Pharmacokinetics · doi:10.1016/j.dmpk.2022.100481 · Cited by 8 · see citing works
Bioavailability of Long Acting Capsules of Melatonin in Mexican Healthy Volunteers
Gamboa, M. L., Canales-Gómez, J. S., & Sandoval, T. D. J. C. (2010) · Journal of Bioequivalence & Bioavailability · doi:10.4172/jbb.1000042 · Cited by 8 · see citing works
Ansari‐Pour, N. (2011) · Doctoral thesis, UCL (University College London). · Cited by 7 · see citing works
Iwashita, H., Sano, M., & Chiba, A. (2022) · Hormones and Behavior · doi:10.1016/j.yhbeh.2023.105329 · Cited by 6 · see citing works
Showande, S. J., Igbinoba, S. I., Kajula, M., Hokkanen, J., Tolonen, A., Adegbolagun, O. M., & Fakeye, T. O. (2019) · Journal of Basic and Clinical Physiology and Pharmacology · doi:10.1515/jbcpp-2018-0206 · Cited by 6 · see citing works
Cytochrome P450 enzymes— in vitro , in vivo , and in silico studies
Turpeinen, M. (2006) · Cited by 6 · see citing works
Melatonin and retinal cell damage: molecular and biological functions
Sun, J., Liu, Y., & Chen, Z.-M. (2024) · Naunyn-Schmiedeberg's Archives of Pharmacology · doi:10.1007/s00210-024-03575-w · Cited by 5 · see citing works
“The liver has the ability to convert melatonin into N-acetylserotonin (NAS) via the enzymes CYP2C19 or CYP1A, which is a less important metabolic pathway (Facciolá et al. 2001; Semak et al. 2008).”
Alzheimer's Disease: Focus on the Neuroprotective Role of Melatonin
Srinivasan, V., Lauterbach, E. C., Ahmed, A. H., & Prasad, A. (2012) · Journal of Neurology Research · doi:10.4021/jnr.v2i3.93 · Cited by 6 · see citing works
“Although these actions are observed at pharmacological concentrations, the relevance of these findings can be appreciated if one considers the relatively high rates of melatonin secretion into the CSF, uptake into the brain tissue and metabolization of melatonin into other neuroprotective compounds such as the kynuram…”
BackgroundPharmacogenetic Gene–Drug Associations in Pediatric Burn and Surgery Patients
Grimsrud, K., Davis, R. R., Tepper, C. G., et al. (2022) · Journal of Burn Care & Research · doi:10.1093/jbcr/irac062 · Cited by 5 · see citing works
Trazodone Hypnotic Effect and Nocturnal Melatonin Secretion
Morera, A. M., Abreu-González, P., Henry, M., & Garcia-Hernandez, A. (2009) · Journal of Clinical Psychopharmacology · doi:10.1097/jcp.0b013e318192e05c · Cited by 5 · see citing works
Melatonin As An Antioxidant Agent In Disease Prevention: A Biochemical Focus
Akhzari, M., Barazesh, M., & Jalili, S. (2022) · Letters in Organic Chemistry · doi:10.2174/1570178619666220325124451 · Cited by 6 · see citing works
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“Other CYP450s involved, to a lesser extent, in the enzymatic degradation of melatonin into 6-hydroxymelatonin are CYP2C9 and CYP2C19 [15].”
Background
- Authors
- Facciolá, G., Hidestrand, M., von Bahr, C., & Tybring, G.
- Affiliations
- Karolinska Institutet (SE)
- Venue
- European Journal of Clinical Pharmacology
- Published
- 2001-02-01
- Volume
- 56
- Issue
- 12
- Pages
- 881-888
- ISSN
- 0031-6970 (ISSN-L)
- 1432-1041
- OpenAlex
- W2025502084
- Semantic Scholar
- 75bffaa408d11f2d1001468f2f48f70361763b15
- Cited by
- 126
- References
- 0
- Citations by year
- 2026: 3 · 2024: 2 · 2023: 4 · 2022: 7 · 2021: 7 · 2020: 5 · 2019: 2 · 2018: 5 · 2017: 3 · 2016: 3 · 2015: 7 · 2014: 7 · 2013: 5 · 2012: 8
- FWCI
- 4.04
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- European Journal of Clinical Pharmacology (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Pharmacogenetics and Drug Metabolism
- Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Circadian rhythm and melatonin
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Eicosanoids and Hypertension Pharmacology
- Keywords
- melatonin metabolism, cytochrome P450, 6-hydroxymelatonin, N-acetylserotonin, CYP1A2, CYP2C9, CYP2C19, human liver microsomes, fluvoxamine, drug interactions, enzyme inhibition, furafylline, omeprazole
- MeSH terms
- Cells, Cultured, Chromatography, High Pressure Liquid, Cytochrome P-450 Enzyme System, Humans, Hydroxylation, Isoenzymes, Melatonin, Microsomes, Liver, Substrate Specificity, Fluvoxamine, Selective Serotonin Reuptake Inhibitors
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