Open AccessInhibitory and Stimulatory Effects of Selective Serotonin Reuptake Inhibitors on Cytochrome P450 2D6-mediated Dopamine Formation from p-Tyramine
Author(s) -
Toshiyuki Niwa,
Shizuya Sugimoto
Publication year - 2019
Publication title -
journal of pharmacy and pharmaceutical sciences
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.497
H-Index - 78
ISSN - 1482-1826
DOI - 10.18433/jpps30622
Subject(s) - cyp2d6 , dopamine , tyramine , fluoxetine , reuptake , paroxetine , chemistry , pharmacology , serotonin , reuptake inhibitor , medicine , endocrinology , biology , biochemistry , cytochrome p450 , metabolism , receptor
PURPOSE: The effects of selective serotonin reuptake inhibitors (SSRIs) such as fluoxetine and paroxetine on dopamine formation from p-tyramine, mediated by cytochrome P450 (CYP) 2D6.2 (Arg296Cys, Ser486Thr) and CYP2D6.10 (Pro34Ser, Ser486Thr), were compared with their effects on CYP2D6.1 (wild type)-mediated dopamine formation, to investigate the influence of a CYP2D6 polymorphism on neuroactive amine metabolism in the brain. METHODS: The Michaelis constants (Km) and maximal velocity (Vmax) values of dopamine formation mediated by CYP2D6.1, CYP2D6.2, and CYP2D6.10 (expressed in recombinant Escherichia coli), and inhibition constants (Ki) of the SSRIs toward dopamine formation catalyzed by the CYP2D6 variants were estimated. RESULTS: The Km values for CYP2D6.2 and CYP2D6.10 decreased at lower fluoxetine concentrations, while the Vmax values for all CYP2D6 variants increased, indicating that fluoxetine stimulated dopamine formation. Conversely, paroxetine competitively inhibited dopamine formation mediated by CYP2D6.1, CYP2D6.2, and CYP2D6.10 with Ki values of 0.47, 1.33, and 31.3 µM, respectively. CONCLUSIONS: These results suggest that the inhibition/stimulation of CYP2D6