Regeneration of serotonin from 5-methoxytryptamine by polymorphic human CYP2D6.

摘要: Polymorphic cytochrome P450 2D6 (CYP2D6) is expressed in several types of central neurons but its function human brain currently unknown. Using recombinant enzymes and CYP2D6-transgenic mice, we established that 5-methoxytryptamine (5-MT), a metabolite precursor melatonin, specific high-turnover endogenous substrate CYP2D6. This potent serotonergic neuromodulator numerous physiological systems binds tightly to CYP2D6 enzyme with an equilibrium dissociation constant (K(s)) 23.4 micromol/l, O-demethylated serotonin (5-hydroxytryptamine, 5-HT) high turnover 51.7 min(-1) low Michaelis-Menten 19.5 micromol/l. The production 5-HT from 5-MT catalyzed by was inhibited selective reuptake inhibitors, their inhibition potency (K(i), micromol/l) decreased the order fluoxetine (0.411) > norfluoxetine (1.38) fluvoxamine (10.1) citalopram (10.9). Liver microsomes prepared mice showed about 16-fold higher O-demethylase activity than wild-type mice. After intravenous co-administration (10 mg/kg) pargyline (20 mg/kg), serum level 3-fold When dosed alpha,alpha,beta,beta-d -5-MT, alpha,alpha,beta,beta-d4-5-HT detected transgenic mouse serum, content much mouse. not produced pretreated quinidine. regeneration provides missing link serotonin-melatonin cycle. Up 10% population lacks this enzyme. It proposed common inborn error O-demethylation influences range neurophysiologic pathophysiologic events.