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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...

This article focuses on recent research on the cytochrome P450 2D (CYP2D) catalyzed synthesis of the monoaminergic neurotransmitters dopamine and serotonin in the brain and on the influence of psychotropic drugs on the activity of brain CYP2D. Recent in vitro and in vivo studies performed in rodents indicate that dopamine and serotonin may be formed in the brain via alternative CYP2D-mediated pathways, i.e., tyramine hydroxylation and 5-methoxytryptamine O-demethylation, respectively. The contribution of these alternative pathways to the total synthesis of brain neurotransmitters may be higher in humans and may be significantly increased under specific conditions, such as tyrosine hydroxylase and amino acid decarboxylase or tryptophan hydroxylase deficiency. These alternative pathways of neurotransmitter synthesis may also become more efficient when the CYP2D enzyme is mutated or activated by inducers (e.g., alcohol, nicotine, psychotropics), which may be of importance in some neurodegenerative or psychiatric diseases. In addition to the previously observed influence of antidepressants and neuroleptics on CYP2D in the liver, the investigated drugs also produce an effect on CYP2D in the brain. However, their effect on brain CYP2D is different than that in the liver and is structure-dependent. The observed psychotropic drug-brain CYP2D interactions may be important for the metabolism of endogenous neuroactive substrates (e.g., monoaminergic neurotransmitters, neurosteroids) and for the local biotransformation of drugs. The results are discussed with regard to the contribution of CYP2D to the total synthesis of neurotransmitters in the brain in vivo as well as the possible significance of these alternative pathways in specific physiological and pathological conditions and in the pharmacological actions of psychotropic drugs.