METABOLISM OF MELATONIN BY HUMAN CYTOCHROMES P450

• Published in: Drug metabolism and disposition Vol. 33; no. 4; pp. 489 - 494
• Main Authors: Ma, Xiaochao, Idle, Jeffrey R., Krausz, Kristopher W., Gonzalez, Frank J.
• Format: Journal Article
• Language: English
• Published: Bethesda, MD Elsevier Inc 01.04.2005; American Society for Pharmacology and Experimental Therapeutics
• Subjects: Animals; Aryl Hydrocarbon Hydroxylases - genetics; Aryl Hydrocarbon Hydroxylases - metabolism; Biological and medical sciences; Brain - enzymology; Brain - metabolism; Chromatography, Liquid; Cytochrome P-450 CYP1B1; Cytochrome P-450 Enzyme System - genetics; Cytochrome P-450 Enzyme System - metabolism; DNA, Complementary - genetics; Humans; Hydroxylation; In Vitro Techniques; Isoenzymes - metabolism; Male; Mass Spectrometry; Medical sciences; Melatonin - metabolism; Mice; Mice, Knockout; Pharmacology. Drug treatments; Human; Melatonin; Enzyme; Cytochrome P450; Pharmacokinetics; Metabolism; Pineal hormone
• ISSN: 0090-9556; 1521-009X
• DOI: 10.1124/dmd.104.002410

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 Km (μM) and Vmax (kcat, 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.