The neuroendocrine regulation of hepatic cytochrome P450 by NMDA receptors in the paraventricular and arcuate nuclei of the hypothalamus

Our previous study showed that the antagonist of the GluN2B subunit of the N-methyl-D-aspartate (NMDA) receptor, the compound CP-101,606, negatively affected hepatic cytochrome P450 (P450) expression and activity after intraperitoneal administration. The aim of our current study was to demonstrate the effect of intracerebral administration of CP-101,606 into the paraventricular (PVN) or arcuate (ARC) nuclei of the hypothalamus on the central neuroendocrine regulation of P450. Male rats received bilateral injections of CP-101,606 into the PVN or ARC for 5 days. Hypothalamic, pituitary, and serum hormone levels, and the expression and activity of hepatic P450 enzymes were measured. Repeated injections of CP-101,606 into the PVN increased somatostatin levels in the PVN and pituitary, decreased serum growth hormone (GH) and corticosterone but raised T3 concentration, followed by a reduction in the expression (mRNA and protein levels) and activity of CYP1A1/2, CYP2A1/2, CYP2B1/2, CYP2C11, and CYP3A activity in the liver. Multiple administration of CP-101,606 into the ARC decreased GH-releasing hormone level in the ARC and pituitary, and reduced serum GH and corticosterone levels without changes in thyroid hormones. This led to a decline in the expression and activities of hepatic CYP1A1/2 and CYP2C11, and the CYP3A2 mRNA levels. The obtained results show an important role of NMDA receptors of the PVN and ARC in the regulation of hepatic P450 enzymes. They indicate a negative effect of CP-101,606 on the central neuroendocrine regulation of P450 enzymes, which should be taken into account when introducing new drugs antagonizing the GluN2B subunit of the NMDA receptor. SIGNIFICANCE STATEMENT: The results indicate an important role of GluN2B subunit-containing N-methyl-D-aspartate (NMDA) receptors present in the hypothalamic paraventricular and arcuate nuclei in the central neuroendocrine regulation of cytochrome P450 expression and activity in the rat liver. Further clinical studies are advisable to show whether antagonists of the NMDA receptor GluN2B subunit affect cytochrome P450 drug-metabolizing enzymes in the human liver. This issue may be particularly relevant when combining an NMDA antagonist with other drugs in the treatment of psychiatric or neurological diseases.