Abstract
Recent research indicates that selective NMDA receptor GluN2B subunit antagonists may become useful for the treatment of major depressive disorders. We aimed to examine in parallel the effect of the selective NMDA receptor GluN2B subunit antagonist CP-101,606 on the pituitary/serum hormone levels and on the regulation of cytochrome P450 in rat liver. CP-101,606 (20 mg/kg ip. for 5 days) decreased the activity of CYP1A, CYP2A, CYP2B, CYP2C11 and CYP3A, but not that of CYP2C6. The alterations in enzymatic activity were accompanied by changes in the CYP protein and mRNA levels. In parallel, a decrease in the pituitary growth hormone-releasing hormone, and in serum growth hormone and corticosterone (but not T3 and T4) concentration was observed. After a 3-week administration period of CP-101,606 less changes were found. A decrease in the CYP3A enzyme activity and protein level was still maintained, though no change in the mRNA level was found. A slight decrease in the serum concentration of corticosterone was also maintained, while GH level returned to the control value. The obtained results imply engagement of the glutamatergic system in the neuroendocrine regulation of cytochrome P450 and potential involvement of drugs acting on NMDA receptors in metabolic drug–drug interactions.
Highlights
Knowledge of the regulation of liver cytochrome P450 by drugs and toxic substances at the level of the hepatocyte is already broad, physiological regulation of its expression, especially the role of the nervous system has been the subject of research only for the last decade
When the enzyme activity was changed, the effect of CP-101,606 on the enzyme expression was tested to find the mechanism of regulation
The obtained results imply the contribution of NMDA glutamate receptors to the neuroendocrine regulation of cytochrome P450 expression
Summary
Knowledge of the regulation of liver cytochrome P450 by drugs and toxic substances at the level of the hepatocyte is already broad, physiological regulation of its expression, especially the role of the nervous system has been the subject of research only for the last decade. Since secretion of hormones regulating cytochrome P450 genes (e.g., growth hormone, corticosterone and thyroid hormones) is under the control of the brain nervous system (mostly by the hypothalamus), the changes in brain neurotransmission can affect endocrine regulation of cytochrome P450 in the liver. The neuroendocrine regulation of cytochrome P450 has already been shown to occur via the brain dopaminergic [1,2,3], noradrenergic [4,5,6] and serotonergic [7,8,9,10,11,12,13] systems
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