Involvement of the paraventricular (PVN) and arcuate (ARC) nuclei of the hypothalamus in the central noradrenergic regulation of liver cytochrome P450.
The present study was aimed at assessing the influence of noradrenergic innervation of the paraventricular nucleus (PVN) and the arcuate nucleus (ARC) of the brain hypothalamus on cytochrome P450 expression in the liver. DSP-4, a neurotoxin specific to noradrenergic nerve terminals, was administrated locally into the PVN or ARC. One week after neurotoxin injection, the levels of neurotansmitters (noradrenaline/dopamine/serotonin) were measured in the middle part of the hypothalamus, hormone concentrations were estimated in blood plasma, and the activity and the protein levels of CYP isoforms were measured in the liver. A significant decrease in noradrenaline level in the hypothalamus was observed after DSP-4 injection into the PVN or ARC. The levels of dopamine or serotonin remained unchanged or slightly lowered. Simultaneously, significant changes in the plasma concentration of growth hormone were found; its elevation in PVN-lesioned rats and a drop in ARC-lesioned ones. There were no changes in the plasma concentration of the thyroid hormones or corticosterone. The activity and protein levels of isoforms CYP2C11, CYP3A and CYP2A rose in the liver of PVN-lesioned rats, but the activity and protein level of CYP2C11 fell in ARC-lesioned animals such a tendency being also observed in the case of CYP3A. Our study shows that noradrenergic innervation of the PVN and ARC of the hypothalamus exerts an opposite effect on the regulation of cytochrome P450 in the liver. These findings may be important for pharmacological experiments and pharmacotherapy with neuroactive drugs, since cytochrome P450 is responsible for the metabolism of steroids and the majority of drugs.
Institute of Pharmacology, Polish Academy of Sciences, Smętna 12, 31-343 Kraków, Poland.
Ewa
E
Bromek
Jacek
J
Wójcikowski
Władysława A
WA
Daniel
D059331:Adrenergic Neurons / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D001111:Arcuate Nucleus of Hypothalamus / Q000187:drug effects / Q000378:metabolism*; D001596:Benzylamines / Q000494:pharmacology; D003345:Corticosterone / Q000097:blood; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis / Q000378:metabolism*; D004298:Dopamine / Q000378:metabolism; D007527:Isoenzymes; D008099:Liver / Q000201:enzymology*; D008297:Male; D009498:Neurotoxins / Q000494:pharmacology; D009638:Norepinephrine / Q000378:metabolism*; D010286:Paraventricular Hypothalamic Nucleus / Q000187:drug effects / Q000378:metabolism*; D051381:Rats; D011919:Rats, Inbred Strains; D012701:Serotonin / Q000378:metabolism; D013963:Thyroid Hormones / Q000097:blood
D001596:Benzylamines; D007527:Isoenzymes; D009498:Neurotoxins; D013963:Thyroid Hormones; D012701:Serotonin; D003577:Cytochrome P-450 Enzyme System; C012102:DSP 4; D004298:Dopamine; D003345:Corticosterone; D009638:Norepinephrine
5-HT; ACTH; ARC; CRH; CYP; DA; DSP-4; Endogenous hormones; GH; GHRH; HPA; HPLC; N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine; NA; Noradrenergic neurotoxin DSP-4; PVN; Paraventricular and arcuate nuclei; PeV; Rat brain noradrenaline; Rat liver cytochrome P450; SRIH; T(3); T(4); TRH; TSH; adrenocorticotropic hormone; arcuate nucleus; corticotropin-releasing hormone; cytochrome P450; dopamine; growth hormone; growth-hormone-releasing hormone; high performance liquid chromatography; hypothalamo-pituitary axis; noradrenaline; paraventricular nucleus; periventricular subnucleus of PVN; serotonin; somatostatin; thyroid-stimulating hormone; thyrotropin-releasing hormone; thyroxine; triiodothyronine