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

2019 ◽  
Vol 22 ◽  
pp. 585-592
Author(s):  
Toshiro Niwa ◽  
Shizuya Sugimoto
Keyword(s):  
Cytochrome P450 ◽  
Serotonin Reuptake ◽  
Selective Serotonin Reuptake Inhibitors ◽  
Serotonin Reuptake Inhibitors ◽  
Selective Serotonin ◽  
Maximal Velocity ◽  
Cyp2d6 Polymorphism ◽  
Amine Metabolism ◽  
Michaelis Constants ◽  
The Brain

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

Debate resolved: there are differential effects of serotonin selective reuptake inhibitors on cytochrome P450 enzymes

1998 ◽  
Vol 12 (4_suppl) ◽  
pp. S89-S97 ◽  
Author(s):  
Sheldon H. Preskorn
Keyword(s):  
Cytochrome P450 ◽  
Plasma Levels ◽  
Serotonin Reuptake ◽  
Selective Serotonin Reuptake Inhibitors ◽  
Serotonin Reuptake Inhibitors ◽  
Original Position ◽  
Selective Serotonin ◽  
Cytochrome P450 Enzymes ◽  
Extensive Body ◽  
Cyp 2D6

In 1993, it was first proposed that an important difference between selective serotonin reuptake inhibitors (SSRIs) was the degree of inhibition of the cytochrome P450 (CYP) enzyme 2D6 that they produced under usually dosing conditions (Preskorn, 1993). Specifically, fluoxetine and paroxetine, in contrast to sertraline, were identified as causing substantial increases in the plasma levels of coadministered drugs, which were principally dependent on CYP 2D6 for their metabolism. Over the next 5 years, this position was hotly contested (Preskorn and Nemeroff, 1997). However, an extensive body of research has now accumulated, which incontrovertibly supports the original position. This paper will reviews this research and extends the discussion to all five SSRIs and four other important CYP enzymes: 1A2, 2C9/10, 2C19, and 3A3/4.

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

2018 ◽  
Vol 21 ◽  
pp. 135-142
Author(s):  
Toshiro Niwa ◽  
Mayumi Yanai ◽  
Maya Matsumoto ◽  
Marina Shizuku
Keyword(s):  
Cytochrome P450 ◽  
Inhibitory Action ◽  
Maximal Velocity ◽  
Wild Type ◽  
Inhibitory Effects ◽  
Cyp2d6 Polymorphism ◽  
Amine Metabolism ◽  
The Brain ◽  
Cyp 2D6 ◽  
Stimulation Of

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 non-competitively 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. This article is open to POST-PUBLICATION REVIEW. Registered readers (see “For Readers”) may comment by clicking on ABSTRACT on the issue’s contents page.

Cytochrome P450 genotype and aggressive behavior on selective serotonin reuptake inhibitors

2018 ◽  
Vol 19 (14) ◽  
pp. 1097-1099
Author(s):  
Corine Ekhart ◽  
Maja Matic ◽  
Agnes Kant ◽  
Laure Elens ◽  
Eugène van Puijenbroek ◽  
...  
Keyword(s):  
Cytochrome P450 ◽  
Aggressive Behavior ◽  
Serotonin Reuptake ◽  
Selective Serotonin Reuptake Inhibitors ◽  
Serotonin Reuptake Inhibitors ◽  
Selective Serotonin
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