The reverse role of the hypothalamic paraventricular (PVN) and arcuate (ARC) nuclei in the central serotonergic regulation of the liver cytochrome P450 isoform CYP2C11.

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.