Effect of Cytochrome P450 (CYP) 2D6 Genetic Polymorphism on the Inhibitory Action of Antidepressants on CYP2D6-Mediated Dopamine Formation from p-Tyramine

Abstract

-PURPOSE: The inhibitory effects of antidepressants, such as imipramine, desipramine, and fluvoxamine, on dopamine formation from p-tyramine catalyzed by cytochrome P450 (CYP) 2D6.2 (Arg296Cys, Ser486Thr) and CYP2D6.10 (Pro34Ser, Ser486Thr), were compared with those on dopamine formation catalyzed by CYP2D6.1 (wild type), to investigate the effect of a CYP2D6 polymorphism on neuroactive amine metabolism in the brain. METHODS: Inhibition constants (Ki) of the antidepressants toward dopamine formation catalyzed by CYP2D6.1, CYP2D6.2, and CYP2D6.10, which were expressed in recombinant Escherichia coli, were compared. RESULTS: Imipramine and desipramine competitively or noncompetitively inhibited dopamine formation mediated by CYP2D6.1, CYP2D6.2, and CYP2D6.10 with Ki values of 3.9-4.9, 5.9-9.6, and 26.7-37.5 µM, respectively. The maximal velocity (Vmax) values for dopamine formation by all CYP2D6 variants gradually increased with increasing fluvoxamine concentrations up to 40-100 µM, indicating that fluvoxamine stimulated dopamine formation. CONCLUSIONS: These results suggest that the inhibition/stimulation of CYP2D6-mediated dopamine formation by these antidepressants would be affected by CYP2D6 polymorphism in the brain.

Inhibitory and Stimulatory Effects of Selective Serotonin Reuptake Inhibitors on Cytochrome P450 2D6-mediated Dopamine Formation from p-Tyramine

“…However, fluoxetine increased the Km and Vmax values of CYP2D6mediated progesterone 21-hydroxylation (40). Imipramine and desipramine inhibited dopamine formation from p-tyramine and the Ki values for CYP2D6.10 were higher than those for CYP2D6.1 (25). In this study, paroxetine inhibited dopamine formation with a higher Ki value for CYP2D6.10 compared with that for CYP2D6.1.…”

“…This activation has similarly been demonstrated for other P450s such as CYP1A2, CYP2C8, CYP2C9, CYP2D6, and CYP3A7 (42). We previously observed that fluoxetine increased the Km and Vmax values for CYP2D6-mediated progesterone 21-hydroxylation (40), and that fluvoxamine and other SSRIs increased the Km and Vmax values for dopamine formation mediated by CYP2D6.1, CYP2D6.2, and CYP2D6.10, but decreased the Km value for CYP2D6.10 to the level for CYP2D6.1 and CYP2D6.2 (25). Fluoxetineinduced activation of CYP2D6-mediated progesterone 21-hydroxylation was the first finding in relation to CYP2D6 (40,42).…”

“…10 (25). Conversely, Vmax values for dopamine formation by all CYP2D6 variants gradually increased with increasing concentrations of fluvoxamine, indicating that fluvoxamine stimulated dopamine formation (25). Fluvoxamine is a selective serotonin reuptake inhibitor (SSRI) widely used in the treatment of depression to overcome the toxicity of older generation antidepressants (22,23,(26)(27)(28)(29).…”

Pharmacogenomics in Psychiatry Practice: The Value and the Challenges

“…For instance, PMs have a greater DA tone in the pituitary gland, combined with a lower serotonin tone, due to serotonin-mediated tonic inhibition [ 74 ]. Overall, the contributions of CYP2D6 and CYP2C19 in the metabolism of endogenous substances are not fully understood, and further investigations are required to prove the physiological implications of CYP450 in the brain [ 69 , 72 , 75 ].…”

Penambatan Molekul Senyawa Volatil Ekstrak Diklorometana Sambiloto Terhadap Jalur Pensinyal Epidermal Growth Factor Receptor

“…Sifat Fisikokimia beta-amirin dan stigmasterol Tabel 3 dalam penelitian ini menggambarkan bahwa kedua senyawa tersebut memiliki laju absorpsi yang lambat dengan menganalisis plot boiled-egg (Daina & Zoete, 2016). Beta-amirin merupakan inhibitor dari sitokrom P450 yang berperan sebagai katalis reaksi oksidasi seperti obat eksogen dan karsinogen, ataupun senyawa yang bersifat toksik (Niwa, Yanai, Matsumoto, & Shizuku, 2019). Hal ini menandakan bahwa beta-amirin dapat diproses secara fisiologis oleh enzim sitokrom P450 CYP2C9.…”