Role of amino acids at positions 34, 296, and 486 of cytochrome P450 2D6 in the stimulatory and inhibitory effects of psychotropic agents on dopamine formation from <i>p</i>-tyramine

My research focused on the effects of various drugs on (1) dopamine formation from p-tyramine catalyzed by polymorphic cytochrome P450 (CYP or P450) 2D6 variants and (2) endogenous steroid hormone hydroxylation catalyzed by CYP3A subfamily members (CYP3A4, CYP3A5, CYP3A7). The activation (cooperativity) of metabolic reactions catalyzed by P450s was especially emphasized. The effects of various psychotropic agents on dopamine formation from p-tyramine, catalyzed by wild-type CYP2D6.1 and CYP2D6 variants, including CYP2D6.2 (Arg296Cys;Ser486Thr), CYP2D6.10 (Pro34Ser;Ser486Thr), and CYP2D6.39 (Ser486Thr) were compared. Michaelis (K m ) and inhibition (K i ) constants of the psychotropic agents in the presence of CYP2D6.10 were higher than those observed in the presence of other CYP2D6 variants. Fluvoxamine, fluoxetine, milnacipran, and haloperidol activated CYP2D6-catalyzed dopamine formation [decreasing the K m and/or increasing the maximal velocity (k cat )], and this activation was CYP2D6 variant-dependent. Regarding the CYP3A subfamily, the effects of various compounds including endogenous steroid hormones on the 6β-hydroxylation of steroid hormones, such as testosterone, progesterone, and cortisol, were determined; it was found that testosterone, dehydroepiandrosterone, and/ or α-naphthoflavone activated 6β-hydroxylation of cortisol and/or progesterone, but the effects varied in the presence of different CYP3A subfamily members. Further studies are required to confirm the mechanisms and therapeutic relevance of these activation phenomena.

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Stimulatory and Inhibitory Effect of Antipsychotic Agents Including Dopaminergic Neuro-depressants on Dopamine Formation from p-tyramine Mediated by Cytochrome P450 2D6

Niwa,

Yamamoto

2024

DMBL

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Background and Objectives: The effects of antipsychotic agents, including dopamine D2 receptor blocking agents such as haloperidol, chlorpromazine, and sulpiride, and related compounds such as mirtazapine and sertraline, on dopamine formation from p-tyramine catalyzed by cytochrome P450 (CYP) 2D6.2 (Arg296Cys;Ser486Thr), CYP2D6.10 (Pro34Ser;Ser486Thr), and CYP2D6.39 (Ser486Thr) were compared with those of CYP2D6.1. Methods: Dopamine was determined by high-performance liquid chromatography, and Michaelis constants (Km), maximal velocity (kcat) values for dopamine formation, and inhibition constants (Ki) of psychotropic agents were estimated. Results: Km values for all CYP2D6 variants decreased at lower concentrations, and kcat values for CYP2D6 variants except for CYP2D6.10 gradually increased with increasing haloperidol concentrations up to 5 or 10 μM. The kcat/Km values for all CYP2D6 variants increased at under 2.5 μM concentrations. Lower sertraline concentrations decreased Km values for CYP2D6.10. Chlorpromazine at concentrations under 10 µM competitively inhibited the activities catalyzed by all variants; however, the activities for only CYP2D6.10 were increased by chlorpromazine at concentrations over 250 µM. Mirtazapine and sertraline similarly decreased dopamine formation among all variants except for CYP2D6.10. However, CYP2D6.10 inhibition by mirtazapine was weaker than that of the other variants, and sertraline decreased Km values for CYP2D6.10. Conclusion: Haloperidol and sertraline, but not sulpiride, decreased the Km and/or increased kcat values for CYP2D6. The present findings suggest that Dopamine D2 receptor-blocking agents and related compounds may polymorphically affect dopamine formation catalyzed by CYP2D6 in the brain.

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Role of amino acids at positions 34, 296, and 486 of cytochrome P450 2D6 in the stimulatory and inhibitory effects of psychotropic agents on dopamine formation from p-tyramine

Cited by 3 publications

References 30 publications

Effect of Human Cytochrome P450 2D6 Polymorphism on Progesterone Hydroxylation

Effect of Human Cytochrome P450 2D6 Polymorphism on Progesterone Hydroxylation

ヒト薬物代謝酵素シトクロムp450（cyp）2d6及びcyp3aサブファミリーの代謝反応及び内在性ステロイドホルモンなどによる相互作用

Stimulatory and Inhibitory Effect of Antipsychotic Agents Including Dopaminergic Neuro-depressants on Dopamine Formation from p-tyramine Mediated by Cytochrome P450 2D6

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