The role of the nervous system in the regulation of liver cytochrome p450

Abstract

The central and peripheral nervous systems are important factors influencing the functioning of liver cytochrome P450 (CYP). It has been shown that changes in the brain monoaminergic systems affect liver cytochrome P450 (CYP) expression (CYP1A, CYP2B, CYP2C11 and CYP3A). The brain dopaminergic system has been established as an important center regulating the liver CYP. This regulation proceeds via the tuberoinfundibular pathway and the dopaminergic D2 receptors of the pituitary, as well as the mesolimbic pathway engaging the D2 receptors of the nucleus accumbens (conveying a message to the paraventricular nucleus of the hypothalamus). These two dopaminergic pathways stimulate the secretion of pituitary hormones, which directly (GH) or indirectly (ACTH, TSH) activate hepatic nuclear/ cytosolic receptors controlling CYP genes. Recent preliminary studies with selective noradrenaline or serotonin neurotoxins suggest also involvement of the brain noradrenergic and serotonergic systems in the regulation of liver CYP. Moreover, the influence of the peripheral nervous system involving several neurotransmitters (acetylcholine, noradrenaline, adrenaline, dopamine, serotonin) on liver function may also be important for the physiological regulation of hepatic CYP activity. The hypothalamus controls liver function not only by releasing hormones from the pituitary gland but also by stimulating the autonomic sympathetic and parasympathetic projections to the liver. In addition to direct neural connections, the autonomic nervous system can indirectly affect liver function via the hypothalamus-adrenal axis and the hypothalamus- pancreas axis. Therefore, the estimation of neuroactive drug action on hepatic CYP requires an in vivo model which allows the central neuroendocrine and peripheral autonomic regulation of genes coding for CYP isoforms.