Stimulatory and inhibitory effect of antipsychotic agents including dopaminergic neuro-depressants on dopamine formation from p-tyramine mediated by cytochrome P450 2D6

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.