Regulation of liver cytochrome P450 by activation of brain dopaminergic system: physiological and pharmacological implications

The aim of the present study was to investigate the influence of activation of brain dopaminergic system by different dopaminomimetics on the level and activity of liver cytochrome P450 (CYP) isoforms. Studies into the identification of hormones and cytokines which are known to mediate liver CYP expression were also simultaneously carried out.Stimulation of dopaminergic receptors in the pituitary, a target for the tuberoinfundibular pathway, by dopamine (a D₁/D₂ receptor agonist) administered intraperitoneally caused a significant increase in the activities and protein levels of CYP2B, CYP2C11 and CYP3A, a substantial increase in the blood plasma level of growth hormone (GH) and a significant decrease in triiodothyronine (T₃) level. Local stimulation of dopaminergic receptors in the nucleus accumbens, a target for the mesolimbic pathway, by apomorphine (a D₁/D₂ receptor agonist), amphetamine (an indirect D₁/D₂ dopaminemimetic) and quinpirole (a D₂ receptor agonist) produced a substantial rise in CYP3A activity and protein level, caused a large increase in corticosterone concentration and a moderate drop in T₃ level. SKF82958 (a D₁ receptor agonist) did not significantly affect the CYP isoforms or hormones studied. In both cases (activation of the tuberoinfundibular or mesolimbic pathway), the activity and the protein level of CYP1A considerably decreased. Plasma levels of thyroxine, testosterone, interleukin-2 and interleukin-6 were not changed after activation of the two pathways.The obtained results establish the brain dopaminergic system as a physiological centre regulating cytochrome P450 (engaging D₂ receptors and pituitary hormones) and demonstrate new pharmacological aspects of neuroactive drugs that affect this system.