Metabolism of melatonin by human cytochromes p450

Ma, Xiaochao; Idle, Jeffrey R.; Krausz, Kristopher W.; Gonzalez, Frank J.

doi:10.1124/dmd.104.002410

Cited by 319Pharmacogenetics and Drug MetabolismCircadian rhythm and melatoninEicosanoids and Hypertension Pharmacology

Metabolism of melatonin by human cytochromes p450

Ma, Xiaochao, Idle, Jeffrey R., Krausz, Kristopher W., Gonzalez, Frank J.·2005·Drug Metabolism and Disposition

DOI 10.1124/dmd.104.002410

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Abstract

In humans, the pineal hormone melatonin (MEL) is principally metabolized to 6-hydroxymelatonin (6-HMEL), which is further conjugated with sulfate and excreted in urine. MEL O-demethylation represents a minor reaction. The exact role of individual human cytochromes P450 (P450s) in these pathways has not been established. We used a panel of 11 recombinant human P450 isozymes to investigate for the first time the 6-hydroxylation and O-demethylation of MEL. CYP1A1, CYP1A2, and CYP1B1 all 6-hydroxylated MEL, with CYP2C19 playing a minor role. These reactions were NADPH-dependent. CYP2C19 and, to some extent CYP1A2, O-demethylated MEL. The K(m) (microM) and V(max) (k(cat), pmol min(-1) pmol(-1) P450) for 6-hydroxylation were estimated as 19.2 +/- 2.01 and 6.46 +/- 0.22 (CYP1A1), 25.9 +/- 2.47 and 10.6 +/- 0.32 (CYP1A2), and 30.9 +/- 3.76 and 5.31 +/- 0.21 (CYP1B1). These findings confirm the suggestion of others that CYP1A2 is probably the foremost hepatic P450 in the 6-hydroxylation of MEL and a single report that CYP1A1 is also able to mediate this reaction. However, this is the first time that CYP1B1 has been shown to 6-hydroxylate MEL. The IC50 for the CYP1B1-selective inhibitor (E)-2,4,3',5'-tetramethoxystilbene was estimated to be 30 nM for MEL 6-hydroxylation by recombinant human CYP1B1. Comparison of brain homogenates from wild-type and cyp1b1-null mice revealed that MEL 6-hydroxylation was clearly mediated to a significant degree by CYP1B1. CYP1B1 is not expressed in the liver but has a ubiquitous extrahepatic distribution, and is found at high levels in tissues that also accumulate either MEL or 6-HMEL, such as intestine and cerebral cortex, where it may assist in regulating levels of MEL and 6-HMEL.

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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 [292]
Medications that affect CYP1A2, CYP1A1, CYP1B1, and CYP2C19 enzymatic pathways will influence melatonin metabolism.
“Therefore, medications that affect these enzymatic pathways will influence melatonin metabolism.”
From Is Melatonin the “Next Vitamin D”?: A Review of Emerging Science, Clinical Uses, Safety, and Dietary Supplements (2022) · cites this paper as [292]
Melatonin is metabolized via the liver primarily by the enzyme CYP1A2.
“Finally, to underscore the discussion of dosing in both pediatrics and adults, it is important to understand that melatonin is metabolized via the liver primarily by the enzyme CYP1A2 [292].”
From Is Melatonin the “Next Vitamin D”?: A Review of Emerging Science, Clinical Uses, Safety, and Dietary Supplements (2022) · cites this paper as [292]

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Authors: Ma, X., Idle, J. R., Krausz, K. W., & Gonzalez, F. J.
Affiliations: National Cancer Institute (US)
ORCID: Ma, Xiaochao
Idle, Jeffrey R.
Krausz, Kristopher W.
Gonzalez, Frank J.
Venue: Drug Metabolism and Disposition
Publisher: Elsevier BV
Published: 2005-04
Volume: 33
Issue: 4
Pages: 489-494
ISSN: 0090-9556 (ISSN-L)
DOI: 10.1124/dmd.104.002410
OpenAlex: W2099144033
Cited by: 319
References: 37
Citations by year: 2026: 6 · 2025: 21 · 2024: 19 · 2023: 25 · 2022: 31 · 2021: 23 · 2020: 20 · 2019: 18 · 2018: 9 · 2017: 6 · 2016: 11 · 2015: 16 · 2014: 18 · 2013: 13 · 2012: 14
FWCI: 5.37
Type: journal article
Language: en
Open access: closed
Licence: www.elsevier.com/tdm/userlicense/1.0/ (tdm)
www.elsevier.com/legal/tdmrep-license (tdm)
Locations: Drug Metabolism and Disposition (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, 6-hydroxymelatonin, O-demethylation, cytochrome P450, CYP1A1, CYP1A2, CYP1B1, CYP2C19, NADPH-dependent oxidation, pineal gland, hepatic metabolism, sulfation
MeSH terms: Animals, Aryl Hydrocarbon Hydroxylases, Brain, Chromatography, Liquid, Cytochrome P-450 Enzyme System, Humans, Hydroxylation, Isoenzymes, Male, Melatonin, Mass Spectrometry, DNA, Complementary, Mice, Knockout, Mice, Cytochrome P-450 CYP1B1, In Vitro Techniques

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Metabolism of melatonin by human cytochromes p450

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