The regulation of liver cytochrome p450 by the brain dopaminergic system.
Genes encoding different cytochrome P450 (CYP) isoforms are regulated by endogenous hormones (e.g. pituitary hormones, thyroid hormones, glucocorticoids) which are all under control of the central nervous system. The aim of the present study was to investigate the influence of lesions of brain dopaminergic pathways on the level and the activity of CYP isoforms (1A, 2A, 2B, 2C6, 2C11, 2D, 3A) in rat liver. At 48 h after lesion of the tuberoinfundibular pathway, only the activity and the protein level of CYP2B were significantly decreased. Seven days after lesion of the above-mentioned pathway, significant inhibition of CYP2B, CYP2C11 and CYP3A activities and a decrease in CYP protein levels were observed. At the same time, the activity and the protein level of CYP1A considerably increased. Fourteen days after damage of the mesolimbic pathway, the activity and the protein level of CYP3A were significantly reduced, while those of CYP1A were substantially elevated. In contrast, lesion of the nigrostriatal pathway did not affect any CYP isoforms studied. The obtained results provide the first direct evidence for the influence of brain dopaminergic system on the level and the activity of CYP in the liver, which is pathway- and isoform-dependent. Hence stimulation or inhibition of the brain dopaminergic system (e.g. by dopamine receptor-blocking neuroleptics) may cause changes in CYP activity of physiological, pharmacological and toxicological significance, since CYP isoforms that are regulated by the dopaminergic system catalyze the metabolism of endogenous substances (e.g. steroids), clinically important drugs (e.g. psychotropics, calcium channel antagonists, antibiotics) and toxins.
Wójcikowski
Jacek
J
Institute of Pharmacology, Polish Academy of Sciences, Smetna 12, Kraków, Poland. wojcikow@if-pan.krakow.pl
Gołembiowska
Krystyna
K
Daniel
Władysława Anna
WA
D015102:3,4-Dihydroxyphenylacetic Acid / Q000378:metabolism; D000818:Animals; D015153:Blotting, Western; D001921:Brain / Q000502:physiology*; D001923:Brain Chemistry / Q000502:physiology; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000378:metabolism*; D004298:Dopamine / Q000378:metabolism / Q000502:physiology*; D015971:Gene Expression Regulation, Enzymologic / Q000502:physiology*; D006719:Homovanillic Acid / Q000378:metabolism; D066298:In Vitro Techniques; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism; D008032:Limbic System / Q000502:physiology; D008099:Liver / Q000201:enzymology*; D008297:Male; D017072:Neostriatum / Q000502:physiology; D016627:Oxidopamine; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction / Q000502:physiology; D013565:Sympatholytics
D007527:Isoenzymes; D013565:Sympatholytics; D015102:3,4-Dihydroxyphenylacetic Acid; D016627:Oxidopamine; D003577:Cytochrome P-450 Enzyme System; D004298:Dopamine; D006719:Homovanillic Acid