Rysz Marta, Bromek Ewa, Haduch Anna, Liskova Barbora, Wójcikowski Jacek, Daniel Władysława A
Institute of Pharmacology, Polish Academy of Sciences, Smętna 12, 31-343 Kraków, Poland.
Institute of Pharmacology, Polish Academy of Sciences, Smętna 12, 31-343 Kraków, Poland.
Biochem Pharmacol. 2016 Jul 15;112:82-9. doi: 10.1016/j.bcp.2016.04.017. Epub 2016 Apr 29.
Our recent work showed that the brain serotonergic system negatively regulated liver cytochrome P450. The aim of our present research was to study the effect of damage to the serotonergic innervation of the paraventricular (PVN) or arcuate nuclei (ARC) of the hypothalamus on the neuroendocrine regulation of cytochrome P450 (CYP). Male rats received bilateral injections of the serotonergic neurotoxin 5,7-dihydroxytryptamine (5,7-DHT) into the PVN or ARC. One week after the injection brain neurotransmitters, serum hormones (growth hormone, testosterone, corticosterone, thyroid hormones), pituitary somatostatin and liver cytochrome P450 expression and activity were measured. Lesion of the serotonergic innervation of the PVN decreased serotonin level in the hypothalamic area containing the PVN, causing an increase in growth hormone and testosterone concentrations in the blood and, subsequently, an increase in the expression (mRNA and protein level) and activity of isoform CYP2C11 in the liver. In contrast, damage to the serotonergic innervation of the ARC, which caused a decrease in serotonin level in the hypothalamic area containing the ARC, reduced the concentration of growth hormone and the expression and activity of CYP2C11. In conclusion, the obtained results show a reverse effect of the serotonergic innervation of the hypothalamic paraventricular (a negative effect) and arcuate nuclei (a positive effect) on growth hormone secretion and growth hormone-dependent CYP2C11 expression. They also suggest that CYP2C11 expression may be changed by drugs acting via the serotonergic system, their effect depending on their mechanism of action, route of administration (intracerebral, peripheral) and distribution pattern within the hypothalamus.
我们最近的研究表明，大脑血清素能系统对肝细胞色素P450具有负向调节作用。本研究的目的是探讨下丘脑室旁核（PVN）或弓状核（ARC）血清素能神经支配受损对细胞色素P450（CYP）神经内分泌调节的影响。雄性大鼠双侧注射血清素能神经毒素5,7-二羟基色胺（5,7-DHT）至PVN或ARC。注射一周后，检测大脑神经递质、血清激素（生长激素、睾酮、皮质酮、甲状腺激素）、垂体生长抑素以及肝脏细胞色素P450的表达和活性。PVN血清素能神经支配损伤降低了含PVN的下丘脑区域的血清素水平，导致血液中生长激素和睾酮浓度升高，随后肝脏中CYP2C11同工型的表达（mRNA和蛋白质水平）及活性增加相反，ARC血清素能神经支配损伤导致含ARC的下丘脑区域血清素水平降低，降低了生长激素浓度以及CYP2C11的表达和活性。总之，所得结果显示下丘脑室旁核（负向作用）和弓状核（正向作用）的血清素能神经支配对生长激素分泌及生长激素依赖性CYP2C11表达具有相反作用。这些结果还表明，通过血清素能系统起作用的药物可能会改变CYP2C11的表达，其作用取决于药物的作用机制、给药途径（脑内、外周）以及在下丘脑内的分布模式。
