TY - JOUR T1 - METABOLISM OF MELATONIN BY HUMAN CYTOCHROMES P450 JF - Drug Metabolism and Disposition JO - Drug Metab Dispos SP - 489 LP - 494 DO - 10.1124/dmd.104.002410 VL - 33 IS - 4 AU - Xiaochao Ma AU - Jeffrey R. Idle AU - Kristopher W. Krausz AU - Frank J. Gonzalez Y1 - 2005/04/01 UR - http://dmd.aspetjournals.org/content/33/4/489.abstract N2 - 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. The American Society for Pharmacology and Experimental Therapeutics ER -