Brain cytochrome P450 (CYP) contributes to the local metabolism of endogenous substrates and drugs. The aim of present study was to ascertain whether the cytochrome P450 2D (CYP2D) activity changes with ageing and in cerebral serotonin deficit. Kinetics of 5-methoxytryptamine O-demethylation to serotonin was studied and the CYP2D activity was measured in brain and liver microsomes of Dark Agouti wild type (WT) rats (mature 3.5-month-old and senescent 21-month-old rats) and in tryptophan hydroxylase 2 (TPH2)-deficient senescent rats. The CYP2D activity and protein level decreased in the frontal cortex of senescent WT rats, but increased in senescent TPH2-deficient rats (compared to senescent WT). In contrast, in the hippocampus, hypothalamus and striatum the CYP2D activity/protein level increased with ageing, but did not change in senescent TPH2-deficient animals (compared to senescent WT). The activity and protein level of liver CYP2D was lower in senescent WT rats than in the mature animals and further decreased in senescent TPH2-deficient rats. In conclusion, ageing and TPH2-deficit affect the CYP2D activity and protein level, which may have a positive impact on neurotransmitter synthesis in brain structures involved in cognitive, emotional or motor functions, but a negative effect on drug metabolism in the liver.

脑细胞色素 P450 (CYP) 有助于内源性底物和药物的局部代谢。本研究的目的是确定细胞色素 P450 2D (CYP2D) 活性是否随着衰老和脑血清素缺乏而改变。5-甲氧基色胺O的动力学研究了血清素的去甲基化，并在 Dark Agouti 野生型 (WT) 大鼠（成熟 3.5 个月大和衰老 21 个月大的大鼠）和色氨酸羟化酶 2 (TPH2) 的脑和肝微粒体中测量了 CYP2D 活性- 缺乏衰老的老鼠。CYP2D 活性和蛋白质水平在衰老 WT 大鼠的额叶皮层中降低，但在衰老的 TPH2 缺陷大鼠中增加（与衰老 WT 相比）。相比之下，在海马、下丘脑和纹状体中，CYP2D 活性/蛋白质水平随着衰老而增加，但在衰老的 TPH2 缺陷动物中没有变化（与衰老的 WT 相比）。衰老 WT 大鼠肝脏 CYP2D 的活性和蛋白质水平低于成熟动物，并在衰老的 TPH2 缺陷大鼠中进一步降低。综上所述，