The role of brain noradrenergic system in the regulation of liver cytochrome P450 expression.
The aim of the present study was to examine the effect of the brain noradrenergic system on the expression of cytochrome P450 in the liver. The experiment was carried out on male Wistar rats. Intracerebroventricular injection of the noradrenergic neurotoxin DSP-4 diminished noradrenaline level in the brain. Simultaneously, significant decreases in the serum concentration of the growth hormone, testosterone and the thyroid hormone thyroxine, as well as an increase in corticosterone level were observed. The concentrations of triiodothyronine and the cytokines interleukine 2 (IL-2) and 6 (IL-6) were not changed by DSP-4. The neurotoxin produced complex changes in the functioning of cytochrome P450. Significant decreases in the activity of liver CYP2C11 (measured as a rate of the 2α- and 16α-hydroxylation of testosterone) and CYP3A (measured as a rate of the 2β- and 6β-hydroxylation of testosterone) were found. In contrast, the activity of CYP1A (measured as a rate of caffeine metabolism) rose, while that of CYP2A (measured as a rate of the 7α-hydroxylation of testosterone), CYP2C6 (measured as a rate of the 7-hydroxylation of warfarin) and CYP2D (the 1'-hydroxylation of bufuralol) remained unchanged. The changes in the activity of CYP1A, CYP2C11 and CYP3A correlated positively with those in CYP protein levels and with the CYP mRNA levels of CYP1A1, CYP2C11 and CYP3A1/2 genes, respectively. The obtained results indicate an important role of the brain noradrenergic system in the neuroendocrine regulation of liver cytochrome P450 expression, which may be of significance in pathological states involving this system, or during pharmacotherapy with drugs affecting noradrenergic transmission.
Institute of Pharmacology, Polish Academy of Sciences, Smętna 12, 31-343 Kraków, Poland.
Anna
A
Sadakierska-Chudy
Anna
A
Haduch
Marta
M
Rysz
Krystyna
K
Gołembiowska
Władysława A
WA
Daniel
D018663:Adrenergic Agents / Q000633:toxicity*; D000818:Animals; D001596:Benzylamines / Q000633:toxicity*; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D003345:Corticosterone / Q000097:blood; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics* / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D013006:Growth Hormone / Q000097:blood; D007276:Injections, Intraventricular; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism; D008099:Liver / Q000187:drug effects* / Q000201:enzymology; D008297:Male; D009638:Norepinephrine / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D013739:Testosterone / Q000097:blood; D013963:Thyroid Hormones / Q000097:blood
D018663:Adrenergic Agents; D001596:Benzylamines; D007527:Isoenzymes; D013963:Thyroid Hormones; D013739:Testosterone; D013006:Growth Hormone; D003577:Cytochrome P-450 Enzyme System; C012102:DSP 4; D003345:Corticosterone; D009638:Norepinephrine
5-HT; ACTH; AhR; Brain neurotransmitter level; Brain noradrenergic system; CAR; CNS; CRH; CYP; Cytokines; DA; DSP-4; GH; GHR; GHRH; GR; HPLC; Hormones; Liver cytochrome P450 expression; MEE; N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine; NA; Neurotoxin DSP-4; PXR; T(3); T(4); TR; TRH; TSH; adrenocorticotropic hormone; arylhydrocarbon receptor; central nervous system; constitutive androstane receptor; corticotropin-releasing hormone; cytochrome P450; dopamine; glucocorticoid receptor; growth hormone; growth hormone receptor; growth hormone-releasing hormone; high performance liquid chromatography; noradrenaline; pregnane X receptor; serotonin; the external layer of the median eminence; thyroid-stimulating hormone; thyrotropin receptor; thyrotropin-releasing hormone; thyroxine; triiodothyronine