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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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“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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Minich, D. M., Henning, M., Darley, C., Fahoum, M., Schuler, C. B., & Frame, J. (2022) · Nutrients · doi:10.3390/nu14193934 · Cited by 176
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Spaggiari, D., Geiser, L., Daali, Y., & Rudaz, S. L. (2014) · Journal of Pharmaceutical and Biomedical Analysis · doi:10.1016/j.jpba.2014.03.018 · Cited by 100
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Wijnen, P. A. H. M., den Buijsch, R. A. M. O., Drent, M., et al. (2007) · Alimentary Pharmacology & Therapeutics · doi:10.1111/j.1365-2036.2007.03490.x · Cited by 100
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Slominski, A. T., Zmijewski, M. A., Semak, I. V., Zbytek, B., Pisarchik, A. V., Li, W., Zjawiony, J. K., & Tuckey, R. C. (2014) · Anti-Cancer Agents in Medicinal Chemistry · doi:10.2174/18715206113139990308 · Cited by 91
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Jain, S. V., Horn, P. S., Simakajornboon, N., Beebe, D. W., Holland, K. D., Byars, A. W., & Glauser, T. A. (2015) · Sleep Medicine · doi:10.1016/j.sleep.2015.01.005 · Cited by 87
“As melatonin is predominantly metabolized in the liver by cytochrome P450 CYP1A2 and less importantly by CYP2C19 and CYP2C9, there may be individual differences in the metabolism [14,15].”
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Semak, I. V., Корик, Е. О., Antonova, M., Wortsman, J., & Slominski, A. T. (2008) · Journal of Pineal Research · doi:10.1111/j.1600-079x.2008.00630.x · Cited by 80
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BackgroundBackman, J. T., Karjalainen, M. J., Neuvonen, M., Laitila, J., & Neuvonen, P. J. (2006) · British Journal of Clinical Pharmacology · doi:10.1111/j.1365-2125.2006.02653.x · Cited by 59
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Saruwatari, J., Nakagawa, K., Shindo, J., Tajiri, T., Fujieda, M., Yamazaki, H., Kamataki, T., & Ishizaki, T. (2002) · Clinical Pharmacology & Therapeutics · doi:10.1067/mcp.2002.126173 · Cited by 47
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Cardinali, D. P., Pagano, E. S., Bernasconi, P. A. S., Reynoso, R., & Scacchi, P. A. (2011) · PubMed · Cited by 38
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Mise, M., Hashizume, T., Matsumoto, S., et al. (2004) · Pharmacogenetics · doi:10.1097/00008571-200411000-00008 · Cited by 38
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Scheer, F. A. J. L., Cajochen, C., Turek, F. W., & Czeisler, C. A. (2005) · Elsevier eBooks · doi:10.1016/b0-72-160797-7/50039-2 · Cited by 38
Moroni, I., Garcia‐Bennett, A. E., Chapman, J. L., Grunstein, R. R., Gordon, C. J., & Comas, M. (2021) · Sleep Medicine Reviews · doi:10.1016/j.smrv.2021.101431 · Cited by 36
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Karjalainen, M. J., Neuvonen, P. J., & Backman, J. T. (2006) · Drug Metabolism and Disposition · doi:10.1124/dmd.106.011965 · Cited by 35
Poboży, E., Michalski, A., Sotowska-Brochocka, J., et al. (2005) · Journal of Separation Science · doi:10.1002/jssc.200500095 · Cited by 34
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Chang, S., Chen, C., Yang, Z., & Rodrigues, A. D. (2009) · Drug Metabolism and Disposition · doi:10.1124/dmd.109.026997 · Cited by 33
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Markantonis, S. L., Tsakalozou, E., Paraskeva, A., Staikou, ., & Fassoulaki, A. (2007) · The Journal of Clinical Pharmacology · doi:10.1177/0091270007311112 · Cited by 31
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Chojnacki, C. J., Wachowska‐Kelly, P., Błasiak, J., et al. (2012) · Journal of Gastroenterology and Hepatology · doi:10.1111/jgh.12055 · Cited by 29
Mise, M., Hashizume, T., & Komuro, S. (2008) · Drug Metabolism and Disposition · doi:10.1124/dmd.108.022301 · Cited by 29
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Lewis, D. F. V., Lake, B. G., Dickins, M., Ueng, Y., & Goldfarb, P. S. (2003) · Xenobiotica · doi:10.1080/0049825021000048791 · Cited by 28
Chojnacki, C. J., Błasiak, J., Fichna, J., Chojnacki, J., & Popławski, T. (2018) · Molecules · doi:10.3390/molecules23020272 · Cited by 24
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BackgroundShanmugam, R., Barathi, P., Zen, J., et al. (2015) · Electrochimica Acta · doi:10.1016/j.electacta.2015.11.032 · Cited by 22
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Olsen, L. F., Lunding, A., Lauritsen, F. R., et al. (2001) · Biochemical and Biophysical Research Communications · doi:10.1006/bbrc.2001.5047 · Cited by 20
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Panyatip, P., Nunthaboot, N., & Puthongking, P. (2020) · International Journal of Tryptophan Research · doi:10.1177/1178646920978245 · Cited by 19
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Mazzoccoli, G., Kvetnoy, I. M., Mironova, E. S., Yаblonskiy, P. K., Соколович, Е. Г., Krylova, J., Carbone, A., Anderson, G., & Polyakova, V. O. (2021) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2021.111397 · Cited by 19
Shi, S., Shen, Y., Zhao, Z., et al. (2014) · Molecular BioSystems · doi:10.1039/c4mb00360h · Cited by 19
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Chojnacki, C. J., Walecka‐Kapica, E., Klupińska, G., et al. (2012) · Polskie Archiwum Medycyny Wewnętrznej · doi:10.20452/pamw.1371 · Cited by 19
Jiang, W., Tian, X., Wang, Y., Sun, Z., Dong, P., Wang, C., Huo, X., Zhang, B., Huang, S., Deng, S., et al. (2016) · Toxicology Letters · doi:10.1016/j.toxlet.2016.09.004 · Cited by 19
Zhang, L., Huang, W. L., Zhang, Y., et al. (2020) · Frontiers in Microbiology · doi:10.3389/fmicb.2020.00744 · Cited by 18
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Foster, B. C., Cvijovic, K., Boon, H. S., Tam, T. W., Liu, R., Murty, M., Vu, D., Jaeger, W., Tsuyuki, R. T., Barnes, J., et al. (2015) · Journal of Pharmacy & Pharmaceutical Sciences · doi:10.18433/j3ss35 · Cited by 17
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Chojnacki, C. J., Romanowski, M., Winczyk, K., et al. (2012) · Gastroenterology Research and Practice · doi:10.1155/2012/510764 · Cited by 16
Akagi, T., Ushinohama, K., Ikesue, S., et al. (2004) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1124/jpet.103.055657 · Cited by 16
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Ursing, C., Härtter, S., von Bahr, C., Tybring, G., Bertilsson, L., & Röjdmark, S. (2002) · Journal of Endocrinological Investigation · doi:10.1007/bf03344038 · Cited by 15
Self-citationMice convert melatonin to 6-sulphatoxymelatonin
Skene, D. J., Timbers, S. E., Middleton, B., English, J., Kopp, C., Tobler, I., & Ioannides, C. (2006) · General and Comparative Endocrinology · doi:10.1016/j.ygcen.2006.02.009 · Cited by 14
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Bartsch, C., Bartsch, H., & Peschke, E. (2008) · Biological Rhythm Research · doi:10.1080/09291010802066983 · Cited by 12
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Blömeke, B., Golka, K., Griefahn, B., et al. (2008) · Journal of Toxicology and Environmental Health · doi:10.1080/15287390801988020 · Cited by 13
Kolker, D. E., Olson, S. L., Dutton-Boilek, J., Bennett, K. M., Wallen, E. P., Horton, T. H., & Turek, F. W. (2002) · American Journal of Physiology-Regulatory, Integrative and Comparative Physiology · doi:10.1152/ajpregu.00362.2001 · Cited by 13
Ruaño, G., Villagra, D., Rahim, U. S., et al. (2008) · Personalized Medicine · doi:10.2217/17410541.5.6.579 · Cited by 13
Iga, K. (2016) · Journal of Pharmaceutical Sciences · doi:10.1016/j.xphs.2015.11.044 · Cited by 12
Bekała, A., Płotek, W., Siwicka-Gieroba, D., Sołek-Pastuszka, J., Bohatyrewicz, R., Biernawska, J., Kotfis, K., Bielacz, M., Jaroszyński, A., & Dąbrowski, W. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23137094 · Cited by 13
“The degradation of melatonin occurs at the site of its synthesis and in the liver, where the circulating melatonin is metabolized by hepatic cytochrome P-450 enzymes, especially by CYP1A1, CYP1A2, CYP2C19, and CYP2C9 isoforms [51,53,54].”
BackgroundOhki, S., Kunimatsu, M., Ogawa, S., Takano, H., Furihata, T., Shibasaki, H., & Yokokawa, A. (2022) · Chemical and Pharmaceutical Bulletin · doi:10.1248/cpb.c21-00982 · Cited by 11
Chavan, H. D., Li, F., Tessman, R., et al. (2015) · Journal of Biological Chemistry · doi:10.1074/jbc.m114.605386 · Cited by 11
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Morera, A. M., Abreu-González, P., & Henry, M. (2009) · Progress in Neuro-Psychopharmacology and Biological Psychiatry · doi:10.1016/j.pnpbp.2009.05.011 · Cited by 11
Hallam, K. T., Begg, D. P., Olver, J. S., & Norman, T. R. (2008) · Human Psychopharmacology Clinical and Experimental · doi:10.1002/hup.913 · Cited by 10
Lewis, D. F. V., M. Dickins, Lake, B. G., & Goldfarb, P. S. (2003) · Drug metabolism and drug interactions · doi:10.1515/dmdi.2003.19.4.257 · Cited by 10
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Abass, K. M. (2010) · Cited by 10
Wang, X., Yang, F., Zhang, J.-C., et al. (2023) · Plant Cell Reports · doi:10.1007/s00299-022-02969-5 · Cited by 9
Adeyemi, W. J., Abdussalam, T. A., Abdulrahim, H. A., et al. (2020) · Toxicology and Industrial Health · doi:10.1177/0748233720937199 · Cited by 9
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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
Ansari‐Pour, N. (2011) · UCL Discovery (University College London) · Cited by 7
Iwashita, H., Sano, M., & Chiba, A. (2022) · Hormones and Behavior · doi:10.1016/j.yhbeh.2023.105329 · Cited by 6
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
Cytochrome P450 enzymes— in vitro , in vivo , and in silico studies
Turpeinen, M. (2006) · Cited by 6
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
“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
“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
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
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
Laakso, M. ‐., Lindblom, N., Kaipainen, P., et al. (2005) · Scandinavian Journal of Clinical and Laboratory Investigation · doi:10.1080/00365510510025764 · Cited by 4
Moroni, I., & Garcia‐Bennett, A. E. (2021) · Pharmaceutics · doi:10.3390/pharmaceutics13091436 · Cited by 4
“Other CYP450s involved, to a lesser extent, in the enzymatic degradation of melatonin into 6-hydroxymelatonin are CYP2C9 and CYP2C19 [15].”
Background
Metadata
- 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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