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

Drug metabolism and bioanalysis letters Pub Date : 2024-01-01 DOI:10.2174/2949681016666230914115021

Toshiro Niwa, Yuka Yamamoto

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Abstract

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 (K_m), maximal velocity (k_cat) values for dopamine formation, and inhibition constants (Ki) of psychotropic agents were estimated.

Results: K_m 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 k_cat/K_m values for all CYP2D6 variants increased at under 2.5 μM concentrations. Lower sertraline concentrations decreased K_m 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 K_m 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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抗精神病药物（包括多巴胺能神经抑制剂）对细胞色素 P450 2D6 介导的对酪胺形成多巴胺的刺激和抑制作用

背景和目的：抗精神病药物（包括氟哌啶醇、氯丙嗪和舒必利等多巴胺D2受体阻断剂以及米氮平和舍曲林等相关化合物）对细胞色素P450（CYP）2D6催化的对酪胺形成多巴胺的影响。比较了CYP2D6.2（Arg296Cys;Ser486Thr）、CYP2D6.10（Pro34Ser;Ser486Thr）和CYP2D6.39（Ser486Thr）与CYP2D6.1的作用：用高效液相色谱法测定多巴胺，并估算多巴胺形成的迈克尔常数（Km）、最大速度（kcat）和精神药物的抑制常数（Ki）：所有CYP2D6变体的Km值在浓度较低时都会降低，而除CYP2D6.10之外的CYP2D6变体的kcat值会随着氟哌啶醇浓度的增加而逐渐升高，最高可达5或10 μM。当浓度低于 2.5 μM 时，所有 CYP2D6 变体的 kcat/Km 值都会增加。舍曲林浓度越低，CYP2D6.10 的 Km 值越小。氯丙嗪的浓度在 10 μM 以下时，会竞争性地抑制所有变体催化的活性；然而，氯丙嗪的浓度在 250 μM 以上时，只有 CYP2D6.10 的活性会增加。除 CYP2D6.10 外，米氮平和舍曲林同样降低了所有变体的多巴胺形成。然而，米氮平对 CYP2D6.10 的抑制作用弱于其他变体，舍曲林降低了 CYP2D6.10 的 Km 值：氟哌啶醇和舍曲林会降低 CYP2D6.10 的 Km 值和/或增加 kcat 值，但舒必利不会。本研究结果表明，多巴胺 D2 受体阻断剂和相关化合物可能会多态性地影响大脑中由 CYP2D6 催化的多巴胺形成。

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Drug metabolism and bioanalysis letters

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