Cytochrome P450 mediates dopamine formation in the brain in vivo

Abstract

Cytochrome P450 forms (CYPs) of the brain are thought to play a significance role in maintaining brain homeostasis. They are involved in the metabolism of many endogenous substances such as neurosteroids, monoaminergic neurotransmitters, vitamins and arachidonic acid Funae et al. 2003;Yu et al. 2003;Dutheil et al. 2008).Dopamine is formed in the brain from tyrosine via a classic pathway, however, in vitro studies indicate that it may also be produced via tyramine hydroxylation which is catalyzed by the cDNA-expressed human cytochrome P450 form CYP2D6, or human hepatic microsomes (Hiroi et al. 1998). In our study we have demonstrated that this alternative pathway of dopamine formation operates in rat brain microsomes and is catalyzed by the rat cytochrome P450 forms CYP2D2, CYP2D4 (a main rat brain CYP2D form) and CYP2D18; moreover, these rat CYP2D forms are less efficient than human CYP2D6 one in catalyzing the above-described pathway (Bromek et al. 2010). It is therefore possible that the CYP2D-mediated formation of dopamine from tyramine is more important in humans than in rats.The content of cytochrome P450 and its substrate tyramine (derived from food or produced in vivo) in the liver or kidney is relatively high. Therefore, contribution of the CYP2D-pathway to total dopamine biosynthesis in the periphery seems evident (Wassenberg et al. 2010). On the other hand, the production of dopamine from tyrosine in nerves (catalyzed by tyrosine hydroxylase and the aromatic amino acid decarboxylase), as well as from L-DOPA in non-neural peripheral tissues such as the kidney or gastrointestinal tract (catalyzed by aromatic amino acid decarboxylase), is generally lower compared to the brain (Schümann 1956;Bertler and Rosengren 1959;Laverty and Sharman 1965). Aromatic amino acid decarboxylase activity amounts to 14 pmol/min/ mg protein in the kidney (Wassenberg et al. 2010) and to 774 pmol/min/mg protein in the whole brain; the highest activity of the enzyme was found in the hypothalamus and corpus striatum (3585 and 3932 pmol/min/mg protein, AbstractThe cytochrome P450-mediated synthesis of dopamine from tyramine has been shown in vitro. The aim of the present study was to demonstrate the ability of rat cytochrome P450 (CYP) 2D to synthesize dopamine from tyramine in the brain in vivo. We employed two experimental models using reserpinized rats with a blockade of the classical pathway of dopamine synthesis from tyrosine. Model A estimated dopamine production from endogenous tyramine in brain structures in vivo (ex vivo measurement of a tissue dopamine level), while Model B measured extracellular dopamine produced from exogenous tyramine (an in vivo microdialysis). In Model A, quinine (a CYP2D inhibitor) given intraperitoneally caused a significant decrease in dopamine level in the striatum and nucleus accumbens and tended to fall in the substantia nigra and frontal cortex. In Model B, an increase in extracellular dopamine level was observed after tyramine given intrastructurally (the striatum). After joint administrati...

Expression levels of 39 Cyp mRNAs in the mouse brain and neuroblastoma cell lines, C-1300N18 and NB2a – strong expression of Cyp1b1

“…Cyp2d9, 2d10, and 2d22 were also detectable in the mouse neuroblastoma cells. CYP2D6 is involved in the metabolism of psychoactive drugs (Toselli et al, 2016) and the biosynthesis of the important neurotransmitters, dopamine and 5-hydroxytryptamine (Bromek et al, 2011;Idle et al, 2003). SH-SY5Y human neuroblastoma cells express CYP2D6, which may play a role in neuroprotection from Parkinson's disease, which generates neurotoxins in the human brain (Mann and Tyndale, 2010).…”

Cytochrome P450–mediated drug metabolism in the brain

“…63 This study showed that there are sufficient levels of metab olism in the brain to be detected by microdialysis and that this technique may prove to be a useful tool to investigate in vivo brain CYP-mediated metabolism of not only endogen ous neurochemicals, but also of drugs and neurotoxins. Injection of select ive CYP inhibitors into the brain has been used to investigate the mechanism of action of the nonopioid analgesic improgan, and these studies showed that brain CYP epoxygenase activity is required for improgan's analgesic effects.…”

“…Brain CYPs are inducible, and the organ-and brain-region specificity of induction was found to be quite complex. 7,24,43,45,61 This, with the progressive discoveries that brain CYPs can metab olize endogenous neurochemicals, such as tyramine to dopamine by CYP2D6 62,63 and testosterone to 16α-hydroxytestosterone by CYP2B6, 10,64 lent credence to the idea that these enzymes may play a functional role in the brain in both endogenous and exogenous pathways.…”

“…[71][72][73][74] These enzymes are expressed in the brain, and they can all metabolize endogenous neural substrates, suggesting that these genotype-phenotypepersonality associations may be manifested, at least in part, through altered brain metabolism of CNS neurochemicals. CYP2D6 can participate in the metabolism of neurochemicals that influence psychological state, such as the formation of the catecholamines dopamine from tyramine 62,63,75 and serotonin from 5-methoxytryptamine 76,77 and the metabolism of the endogenous cannabinoid anandamide 78 and the neurosteroid progesterone.…”

Human cytochromes P450 in health and disease

“…In human brain, membrane-bound CYP2D6 is localized in pyramidal cells of the cortex and hippocampus, as well as Purkinje cells of the cerebellum. CYP2D-mediated synthesis of dopamine from tyramine has recently been demonstrated to function in brain of the intact rat [61].…”