Institute of Pharmacology, Polish Academy of Sciences, Smętna 12, PL 31-343 Kraków, Poland.
Pharmacol Rep. 2013;65(6):1519-28. doi: 10.1016/s1734-1140(13)71513-5.
This article focuses on recent research on the cytochrome P450 2D (CYP2D) catalyzed synthesis of the monoaminergic neurotransmitters dopamine and serotonin in the brain and on the influence of psychotropic drugs on the activity of brain CYP2D. Recent in vitro and in vivo studies performed in rodents indicate that dopamine and serotonin may be formed in the brain via alternative CYP2D-mediated pathways, i.e., tyramine hydroxylation and 5-methoxytryptamine O-demethylation, respectively. The contribution of these alternative pathways to the total synthesis of brain neurotransmitters may be higher in humans and may be significantly increased under specific conditions, such as tyrosine hydroxylase and amino acid decarboxylase or tryptophan hydroxylase deficiency. These alternative pathways of neurotransmitter synthesis may also become more efficient when the CYP2D enzyme is mutated or activated by inducers (e.g., alcohol, nicotine, psychotropics), which may be of importance in some neurodegenerative or psychiatric diseases. In addition to the previously observed influence of antidepressants and neuroleptics on CYP2D in the liver, the investigated drugs also produce an effect on CYP2D in the brain. However, their effect on brain CYP2D is different than that in the liver and is structure-dependent. The observed psychotropic drug-brain CYP2D interactions may be important for the metabolism of endogenous neuroactive substrates (e.g., monoaminergic neurotransmitters, neurosteroids) and for the local biotransformation of drugs. The results are discussed with regard to the contribution of CYP2D to the total synthesis of neurotransmitters in the brain in vivo as well as the possible significance of these alternative pathways in specific physiological and pathological conditions and in the pharmacological actions of psychotropic drugs.
本文重点介绍了近期关于细胞色素 P450 2D（CYP2D）在大脑中单胺能神经递质多巴胺和 5-羟色胺合成中的作用以及精神药物对脑 CYP2D 活性的影响。最近在啮齿动物中进行的体外和体内研究表明，多巴胺和 5-羟色胺可能分别通过替代 CYP2D 介导的途径，即酪胺羟化和 5-甲氧基色胺 O-脱甲基化在大脑中形成。这些替代途径对脑神经递质总合成的贡献在人类中可能更高，并且在特定条件下（如酪氨酸羟化酶和氨基酸脱羧酶或色氨酸羟化酶缺乏）可能会显著增加。当 CYP2D 酶发生突变或被诱导剂（如酒精、尼古丁、精神药物）激活时，这些神经递质合成的替代途径也可能变得更加高效，这在某些神经退行性或精神疾病中可能很重要。除了先前观察到的抗抑郁药和神经安定药对肝脏中 CYP2D 的影响外，研究中的药物也对大脑中的 CYP2D 产生影响。然而，它们对脑 CYP2D 的影响与在肝脏中的不同，且与结构有关。观察到的精神药物与脑 CYP2D 的相互作用可能对内源性神经活性底物（如单胺能神经递质、神经甾体）的代谢和药物的局部生物转化很重要。结果与 CYP2D 对体内脑神经递质总合成的贡献以及这些替代途径在特定生理和病理条件以及精神药物的药理学作用中的可能意义进行了讨论。
