title: Regeneration of serotonin from 5-methoxytryptamine by polymorphic human CYP2D6.
abstract: Polymorphic cytochrome P450 2D6 (CYP2D6) is expressed in several types of central neurons but its function in human brain is currently unknown. Using recombinant enzymes and CYP2D6-transgenic mice, we established that 5-methoxytryptamine (5-MT), a metabolite and precursor of melatonin, is a specific and high-turnover endogenous substrate of CYP2D6. This potent serotonergic neuromodulator in numerous physiological systems binds tightly to recombinant CYP2D6 enzyme with an equilibrium dissociation constant (K(s)) of 23.4 micromol/l, and is O-demethylated to serotonin (5-hydroxytryptamine, 5-HT) with a high turnover of 51.7 min(-1) and low Michaelis-Menten constant of 19.5 micromol/l. The production of 5-HT from 5-MT catalyzed by CYP2D6 was inhibited by selective serotonin reuptake inhibitors, and their inhibition potency (K(i), micromol/l) decreased in the order of fluoxetine (0.411) > norfluoxetine (1.38) > fluvoxamine (10.1) > citalopram (10.9). Liver microsomes prepared from CYP2D6-transgenic mice showed about 16-fold higher 5-MT O-demethylase activity than that from wild-type mice. After the intravenous co-administration of 5-MT (10 mg/kg) and pargyline (20 mg/kg), serum 5-HT level was about 3-fold higher in CYP2D6-transgenic mice than wild-type mice. When dosed with alpha,alpha,beta,beta-d -5-MT, alpha,alpha,beta,beta-d4-5-HT was detected in transgenic mouse serum, and its content was much higher than wild-type mouse. alpha,alpha,beta,beta-d4-5-HT was not produced in CYP2D6-transgenic mice pretreated with quinidine. The regeneration of 5-HT from 5-MT provides the missing link in the serotonin-melatonin cycle. Up to 10% of the population lacks this enzyme. It is proposed that this common inborn error in 5-MT O-demethylation to serotonin influences a range of neurophysiologic and pathophysiologic events.
authors.affiliation: Laboratory of Metabolism, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Ai-Ming
authors.initials: AM
authors.lastname: Yu
authors.forename: Jeffrey R
authors.initials: JR
authors.lastname: Idle
authors.forename: Linda G
authors.initials: LG
authors.lastname: Byrd
authors.forename: Kristopher W
authors.initials: KW
authors.lastname: Krausz
authors.forename: Adrian
authors.initials: A
authors.lastname: Küpfer
authors.forename: Frank J
authors.initials: FJ
authors.lastname: Gonzalez
mesh_terms: D008735:5-Methoxytryptamine / Q000378:metabolism*; D000818:Animals; D002384:Catalysis; D002851:Chromatography, High Pressure Liquid; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics / Q000378:metabolism*; D065690:Cytochrome P-450 CYP2D6 Inhibitors; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D013058:Mass Spectrometry; D051379:Mice; D008822:Mice, Transgenic; D008862:Microsomes, Liver / Q000201:enzymology; D011110:Polymorphism, Genetic; D013056:Spectrophotometry, Ultraviolet
chemical_list: D065690:Cytochrome P-450 CYP2D6 Inhibitors; D004791:Enzyme Inhibitors; D008735:5-Methoxytryptamine; D019389:Cytochrome P-450 CYP2D6