The role of the dorsal noradrenergic pathway of the brain (locus coeruleus) in the regulation of liver cytochrome P450 activity

Eur J Pharmacol. 2015 Mar 15;751:34-41. doi: 10.1016/j.ejphar.2015.01.014. Epub 2015 Jan 28.

Abstract

Our previous study conducted after intracerebroventricular DSP-4 injection showed an important stimulating role of a brain noradrenergic system in the neuroendocrine regulation of liver cytochrome P450 (CYP) expression. The aim of the present research was to study involvement of the dorsal noradrenergic pathway of the brain (originating from the locus coeruleus) in the expression of liver cytochrome P450. The experiment was carried out on male Wistar rats. Local injection of 6-hydroxydopamine to the locus coeruleus selectively decreased noradrenaline level in the brain (e.g. in the hypothalamus). The serum concentration of the growth hormone rose, while that of the thyroid hormones or corticosterone remained unchanged. A comparative study into cytochrome P450 isoform activity revealed significant increases in the activity of liver CYP2C11 and CYP3A after administration of 6-hydroxydopamine. The observed increase in the activity of CYP2C11 positively correlated with that in CYP protein level, while the enhanced activity of CYP3A was not accompanied with a simultaneous change in the enzyme protein. A 5-day-injection of noradrenaline into the lateral ventricles produced opposite effects on the CYP isoforms. It is concluded that damage to or activation of the dorsal noradrenergic innervation of the periventricular nucleus of the hypothalamus containing somatostatin (a growth hormone release-inhibiting factor) may be responsible for the changes observed in the activity of isoforms CYP2C11 and CYP3A that are regulated by the growth hormone. The obtained results indicate that the dorsal noradrenergic pathway plays an inhibitory (but not a crucial) role in the neuroendocrine regulation of cytochrome P450.

Keywords: 6-Hydroxydopamine; Brain; Cytochrome P450; Liver; Locus coeruleus; Noradrenaline.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cytochrome P-450 Enzyme System / metabolism*
  • Gene Expression Regulation, Enzymologic / drug effects
  • Growth Hormone / blood
  • Injections
  • Lateral Ventricles / drug effects
  • Lateral Ventricles / metabolism
  • Liver / drug effects
  • Liver / enzymology*
  • Locus Coeruleus / drug effects
  • Locus Coeruleus / metabolism*
  • Male
  • Neurotransmitter Agents / metabolism
  • Norepinephrine / administration & dosage
  • Norepinephrine / metabolism*
  • Norepinephrine / pharmacology
  • Oxidopamine / adverse effects
  • Rats
  • Rats, Wistar

Substances

  • Neurotransmitter Agents
  • Oxidopamine
  • Growth Hormone
  • Cytochrome P-450 Enzyme System
  • Norepinephrine