School of Pharmacy, Shujitsu University, 1-6-1 Nishigawara, Naka-ku, Okayama, 703-8516, Japan.
Eur J Drug Metab Pharmacokinet. 2022 Sep;47(5):741-747. doi: 10.1007/s13318-022-00784-7. Epub 2022 Jul 15.
Herein, hydroxylation activities at the 6β-position and 21-position of progesterone mediated by human cytochrome P450 (CYP) 2D6 and its variants and the effects of psychotropic drugs on these hydroxylation activities were compared to clarify whether CYP2D6 polymorphisms and psychotropic drugs impact neurosteroid levels in the brain.
Progesterone was incubated with CYP2D6.1, CYP2D6.2 (Arg296Cys, Ser486Thr), CYP2D6.10 (Pro34Ser, Ser486Thr), and CYP2D6.39 (Ser486Thr) in the absence or presence of typical psychotropic drugs (fluvoxamine, fluoxetine, paroxetine, fluphenazine, and milnacipran) and endogenous steroids (testosterone and cortisol). Then, 6β- and 21-hydroxyprogesterone levels were determined by high-performance liquid chromatography.
Although the Michaelis-Menten constants (K) for progesterone 6β- and 21-hydroxylation reactions mediated by the different CYP2D6 variants were similar, the maximal velocity (V) values of the reactions mediated by CYP2D6.1 and CYP2D6.2 were the highest, followed by those mediated by CYP2D6.39 and CYP2D6.10. Thus, the of progesterone 6β- and/or 21-hydroxylation reactions mediated by CYP2D6.1 and CYP2D6.2 showed the highest V/K values, followed by the reactions mediated by CYP2D6.39. All investigated compounds inhibited progesterone 21-hydroxylation mediated by CYP2D6 variants at high concentrations. Interestingly, at low concentrations, fluoxetine increased progesterone 21-hydroxylation mediated by CYP2D6.1, but not that mediated by CYP2D6.2 or CYP2D6.10. In addition, the K value for CYP2D6.2 was elevated in the presence of fluoxetine, whereas the value for CYP2D6.1 was unaltered; however, V values of both CYP2D6.1 and CYP2D6.2 were increased. Paroxetine competitively inhibited CYP2D6.1- and CYP2D6.2-mediated progesterone 21-hydroxylation.
These results suggest that CYP2D6 polymorphism can affect the stimulation/inhibition of progesterone 21-hydroxylation.
本研究旨在比较人细胞色素 P450（CYP）2D6 及其变体介导的孕酮 6β-位和 21-位羟化活性，以及精神药物对这些羟化活性的影响，以阐明 CYP2D6 多态性和精神药物是否会影响大脑中的神经甾体水平。
在不存在或存在典型精神药物（氟伏沙明、氟西汀、帕罗西汀、氟奋乃静和米那普仑）和内源性甾体（睾酮和皮质醇）的情况下，将孕酮与 CYP2D6.1、CYP2D6.2（Arg296Cys、Ser486Thr）、CYP2D6.10（Pro34Ser、Ser486Thr）和 CYP2D6.39（Ser486Thr）孵育。然后通过高效液相色谱法测定 6β-和 21-羟孕酮水平。
虽然不同 CYP2D6 变体介导的孕酮 6β-和 21-羟化反应的米氏常数（K）相似，但 CYP2D6.1 和 CYP2D6.2 介导的反应的最大速度（V）值最高，其次是 CYP2D6.39 和 CYP2D6.10 介导的反应。因此，CYP2D6.1 和 CYP2D6.2 介导的孕酮 6β-和/或 21-羟化反应的 V/K 值最高，其次是 CYP2D6.39 介导的反应。所有研究的化合物均在高浓度下抑制 CYP2D6 变体介导的孕酮 21-羟化。有趣的是，在低浓度下，氟西汀增加了 CYP2D6.1 介导的孕酮 21-羟化，但不增加 CYP2D6.2 或 CYP2D6.10 介导的孕酮 21-羟化。此外，氟西汀存在时 CYP2D6.2 的 K 值升高，而 CYP2D6.1 的 K 值不变；然而，CYP2D6.1 和 CYP2D6.2 的 V 值均升高。帕罗西汀竞争性抑制 CYP2D6.1 和 CYP2D6.2 介导的孕酮 21-羟化。
这些结果表明，CYP2D6 多态性可影响孕酮 21-羟化的刺激/抑制作用。
