Rysz Marta, Bromek Ewa, Haduch Anna, Sadakierska-Chudy Anna, Daniel Władysława A
Institute of Pharmacology, Polish Academy of Sciences, Kraków, Poland.
Institute of Pharmacology, Polish Academy of Sciences, Kraków, Poland
Drug Metab Dispos. 2015 Sep;43(9):1345-52. doi: 10.1124/dmd.115.064980. Epub 2015 Jun 9.
Genes coding for cytochrome P450 are regulated by endogenous hormones such as the growth hormone, corticosteroids, thyroid, and sex hormones. Secretion of these hormones is regulated by the respective hypothalamus-pituitary-secretory organ axes. Since the brain sends its serotonergic projections from the raphe nuclei to the hypothalamus, we have assumed that damage to these nuclei may affect the neuroendocrine regulation of cytochrome P450 expression in the liver. Thereby, 5,7-dihydroxytryptamine (5,7-DHT), a serotonergic neurotoxin, was injected into the dorsal and median raphe nuclei of male Wistar rats. Ten days after the neurotoxin injections, the brain concentrations of neurotransmitters, serum hormone, and cytokine levels, as well as the expression of cytochrome P450 in the liver were measured. Injection of 5,7-DHT decreased serotonin concentration in the brain followed by a significant rise in the levels of the growth hormone, corticosterone, and testosterone, and a drop in triiodothyronine concentration in the serum. No changes in interleukin (IL) levels (IL-2 and IL-6) were observed. Simultaneously, the activity and protein level of liver CYP1A, CYP3A1, and CYP2C11 rose (the activity of CYP2A/2B/2C6/2D was not significantly changed). Similarly, the mRNA levels of CYP1A1, CYP1A2, CYP2C11, and CYP3A1 were elevated. This is the first report demonstrating the effect of intracerebral administration of serotonergic neurotoxin on liver cytochrome P450. The obtained results indicate involvement of the brain serotonergic system in the neuroendocrine regulation of liver cytochrome P450 expression. The physiologic and pharmacological significance of the findings is discussed.
编码细胞色素P450的基因受内源性激素调控，如生长激素、皮质类固醇、甲状腺激素和性激素。这些激素的分泌受各自的下丘脑 - 垂体 - 分泌器官轴调节。由于大脑从中缝核发出5-羟色胺能投射至下丘脑，我们推测这些核团受损可能会影响肝脏中细胞色素P450表达的神经内分泌调节。因此，将5,7 - 二羟基色胺（5,7 - DHT），一种5-羟色胺能神经毒素，注射到雄性Wistar大鼠的背侧和中缝核中。神经毒素注射十天后，测量大脑中神经递质的浓度、血清激素和细胞因子水平，以及肝脏中细胞色素P450的表达。注射5,7 - DHT降低了大脑中的5-羟色胺浓度，随后生长激素、皮质酮和睾酮水平显著升高，血清中三碘甲状腺原氨酸浓度下降。未观察到白细胞介素（IL）水平（IL - 2和IL - 6）的变化。同时，肝脏CYP1A、CYP3A1和CYP2C11的活性和蛋白水平升高（CYP2A/2B/2C6/2D的活性未显著变化）。同样，CYP1A1、CYP1A2、CYP2C11和CYP3A1的mRNA水平也升高。这是首次报道脑内给予5-羟色胺能神经毒素对肝脏细胞色素P450的影响。所得结果表明大脑5-羟色胺能系统参与肝脏细胞色素P450表达的神经内分泌调节。讨论了这些发现的生理和药理学意义。
