Department of Pharmacokinetics and Drug Metabolism, Maj Institute of Pharmacology, Polish Academy of Sciences, Kraków, Poland.
Max-Delbrück-Center for Molecular Medicine, Berlin, Germany; Institute of Translational Biomedicine, St. Petersburg State University, St. Petersburg, Russia.
Neurochem Int. 2022 Jan;152:105223. doi: 10.1016/j.neuint.2021.105223. Epub 2021 Nov 13.
Among the enzymes that support brain metabolism, cytochrome P450 (CYP) enzymes occupy an important place. These enzymes catalyze the biotransformation pathways of neuroactive endogenous substrates (neurosteroids, neurotransmitters) and are necessary for the detoxification processes. The aim of the present study was to assess changes in the CYP2D activity and protein level during the aging process and as a result of serotonin deficiency in the female brain. The CYP2D activity was measured in brain and liver microsomes of Dark Agouti wild type (WT) female rats (mature 15-week-old and senescent 18-month-old rats) and in tryptophan hydroxylase 2 (TPH2)-deficient senescent female rats. The CYP2D activity in mature WT Dark Agouti females was independent of the changing phases of the estrous cycle. In senescent WT females rats, the CYP2D activity and protein level were decreased in the cerebral cortex, hippocampus, cerebellum and liver, but increased in the brain stem. In the other examined structures (frontal cortex, hypothalamus, thalamus, striatum), the enzyme activity did not change. In aging TPH2-deficient females, the CYP2D activity and protein levels were decreased in the frontal cortex, hypothalamus and brain stem (activity only), remaining unchanged in other brain structures and liver, relative to senescent WT females. In summary, the aging process and TPH2 deficit affect the CYP2D activity and protein level in female rats, which may have a negative impact on the compensatory capacity of CYP2D in the synthesis of serotonin and dopamine in cerebral structures involved in cognitive and emotional functions. In the liver, the CYP2D-catalyzed drug metabolism may be diminished in elderly females. The results in female rats are compared with those obtained previously in males. It is concluded that aging and serotonin deficiency exert sex-dependent effects on brain CYP2D, which seem to be less favorable in females concerning CYP2D-mediated neurotransmitter synthesis, but beneficial regarding slower neurosteroid metabolism.
在支持大脑代谢的酶中，细胞色素 P450（CYP）酶占据重要地位。这些酶催化神经活性内源性底物（神经甾体、神经递质）的生物转化途径，是解毒过程所必需的。本研究旨在评估 CYP2D 活性和蛋白水平在衰老过程中的变化，以及雌性大脑中 5-羟色胺缺乏的结果。在黑毛 Agouti 野生型（WT）雌性大鼠（成熟 15 周龄和衰老 18 月龄大鼠）的大脑和肝脏微粒体中以及色氨酸羟化酶 2（TPH2）缺陷的衰老雌性大鼠中测量了 CYP2D 活性。成熟 WT 黑毛 Agouti 雌性的 CYP2D 活性与发情周期的变化阶段无关。在衰老的 WT 雌性大鼠中，大脑皮质、海马体、小脑和肝脏中的 CYP2D 活性和蛋白水平降低，但脑干中增加。在其他检查的结构（额皮质、下丘脑、丘脑、纹状体）中，酶活性没有变化。在衰老的 TPH2 缺陷雌性大鼠中，CYP2D 活性和蛋白水平在前额皮质、下丘脑和脑干（仅活性）中降低，而在其他脑结构和肝脏中保持不变，与衰老的 WT 雌性大鼠相比。总之，衰老过程和 TPH2 缺乏会影响雌性大鼠的 CYP2D 活性和蛋白水平，这可能对涉及认知和情绪功能的大脑结构中 5-羟色胺和多巴胺合成的 CYP2D 的代偿能力产生负面影响。在肝脏中，CYP2D 催化的药物代谢可能在老年雌性中减少。将雌性大鼠的结果与之前在雄性中获得的结果进行比较。得出的结论是，衰老和 5-羟色胺缺乏对大脑 CYP2D 产生性别依赖性影响，这似乎对雌性的 5-羟色胺合成不利，但对较慢的神经甾体代谢有益。
