Department of Pharmacokinetics and Drug Metabolism, Maj Institute of Pharmacology, Polish Academy of Sciences, Smętna 12, 31-343 Kraków, Poland.
Cells. 2022 Nov 6;11(21):3513. doi: 10.3390/cells11213513.
The aim of this work was to study the effect of prolonged lurasidone administration on the cytochrome 2D (CYP2D) expression and activity in the rat liver and selected brain structures involved in the therapeutic or side effects of this neuroleptic. Male Wistar rats received lurasidone (1 mg/kg ip.) for two weeks. The activity of CYP2D was measured in brain and liver microsomes as the rate of bufuralol 1'-hydroxylation. The CYP2D protein level was determined in microsomes by Western blot analysis. The CYP2D gene expression was estimated in liver tissue by a qRT-PCR method. Lurasidone decreased the activity and protein level of CYP2D in the frontal cortex but increased them in the striatum, nucleus accumbens, brain stem, substantia nigra, and the remainder of the brain. The neuroleptic did not affect CYP2D in the hippocampus, hypothalamus, and cerebellum. In the liver, lurasidone did not affect the CYP2D activity and protein level, though it enhanced the mRNA of without affecting that of , , , and . In conclusion, lurasidone regulates brain (but not liver) CYP2D activity/protein level in a region-dependent manner, which is similar to that of other atypical neuroleptics (iloperidone and asenapine) as concerns the frontal cortex (down-regulation) and nigrostriatal pathway (up-regulation) and may be of pharmacological significance. However, further molecular studies with selective receptor agonists are necessary to find out which individual monoaminergic receptors/signaling pathways are involved in the regulation of the rat CYP2D4 and human CYP2D6 enzyme in particular brain structures.
这项工作的目的是研究长期给予鲁拉西酮对大鼠肝脏中细胞色素 2D（CYP2D）表达和活性的影响，以及该神经安定药的治疗或副作用涉及的选定脑结构。雄性 Wistar 大鼠接受鲁拉西酮（1mg/kg ip.）两周。通过测定脑和肝微粒体中布非洛尔 1'-羟化的速率来测量 CYP2D 的活性。通过 Western blot 分析在微粒体中测定 CYP2D 蛋白水平。通过 qRT-PCR 方法在肝组织中估计 CYP2D 基因表达。鲁拉西酮降低了额皮质中的 CYP2D 活性和蛋白水平，但增加了纹状体、伏隔核、脑干、黑质和脑的其余部分的 CYP2D。神经安定药对海马体、下丘脑和小脑中的 CYP2D 没有影响。在肝脏中，鲁拉西酮不影响 CYP2D 的活性和蛋白水平，但增强了 mRNA 的表达而不影响 、 、 和 的表达。总之，鲁拉西酮以区域依赖性方式调节脑（而非肝脏）CYP2D 活性/蛋白水平，这与其他非典型神经安定药（依匹哌酮和阿塞那平）相似，涉及额皮质（下调）和黑质纹状体通路（上调），可能具有药理学意义。然而，需要进一步进行选择性受体激动剂的分子研究，以确定哪些单独的单胺能受体/信号通路参与调节特定脑结构中的大鼠 CYP2D4 和人 CYP2D6 酶。
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