Abstract
This article focuses on recent research on the cytochrome P450 2D (CYP2D) catalyzed synthesis of themonoaminergic 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 synthesismay also becomemore efficient when the CYP2D enzyme ismutated 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.
Similar content being viewed by others
References
Baum LO, Strobel HW: Regulation of expression of cytochrome P-450 2D mRNA in rat brain with steroid hormones. Brain Res, 1997, 765, 67–73.
Beck O, Jonsson G: In vivo formation of 5-methoxytryptamine from melatonin in rat. J Neurochem, 1981, 36, 2013–2018.
Berry MD: Mammalian central nervous system trace amines. Pharmacologic amphetamines, physiologic neuromodulators. J Neurochem, 2004, 90, 257–271.
Bertilsson L, Alm C, De Las Carreras C, Widen J, Edman G, Schalling D: Debrisoquine hydroxylation polymorphism and personality. Lancet, 1989, 1, 555.
Bromek E, Haduch A, Daniel WA: The ability of cytochrome P450 2D forms to synthesize dopamine in the brain: An in vitro study. Eur J Pharmacol, 2010, 626, 171–178.
Bromek E, Haduch A, Gołembiowska K, Daniel WA: Cytochrome P450-mediates dopamine formation in the brain in vivo. JNeurochem, 2011, 118, 806–815.
Bromek E, Haduch A, Gołembiowska K, Daniel WA: The formation of serotonin from 5-methoxytryptamine via cytochrome P450 in the brain in vivo - a microdialysis study. Eur Neuropsychopharmacol, 2013, 23, Suppl 2, S240–S241.
Chen AR, Irvine RJ, Bochner F, Somogyi AA: Morphine formation from codeine in rat brain: possible mechanism of codeine analgesia. Life Sci, 1990, 46, 1067–1074.
Cheng J, Zhen Y, Miksys S, Beyoglu D, Krausz KW, Tyndale RF, Yu A et al.: Potential role of CYP2D6 in the central nervous system. Xenobiotica, 2013, 43, 973–984.
Chow T, Imaoka S, Hiroi T, Funae Y: Developmental changes in the catalytic activity and expression of CYP2D isoforms in the rat liver. Drug Metab Dispos, 1999, 27, 188–192.
Daniel WA: The influence of long-term treatment with psychotropic drugs on cytochrome P450: the involvement of different mechanisms. Expert Opin Drug Metab Toxicol, 2005, 1, 203–217.
Daniel WA, Haduch A, Wójcikowski J: Inhibition and possibile induction of rat CYP2D after short- and long-term treatment with antidepressants. J Pharm Pharmacol, 2002, 54, 1545–1552.
Daniel WA, Haduch A, Wójcikowski J: Inhibition of rat liver CYP2D in vitro and after 1-day and long-term exposure to neuroleptics in vivo – possible involvement of different mechanisms. Eur Neuropsychopharmacol, 2005, 15, 103–110.
Di Chiara G, Imperato A: Drugs abused by humans preferentially increase synaptic dopamine concentrations in the mesolimbic system of freely moving rats. Proc Natl Acad Sci USA, 1988, 85, 5274–5278.
Ferrari R, Le Novère N, Picciotto MR, Changeux JP, Zoll M: Acute and long-term changes in the mesolimbic dopamine pathway after systemic or local single nicotine injections. Eur J Neurosci, 2001, 15, 1810–1818.
Funae Y, Kishimoto W, Cho T, Niwa T, Hiroi T: CYP2D in the brain. Drug Metab Pharmacokin, 2003, 18, 337–349.
Gonzáles I, Peñas-Lledo, EM, Pérez B, Dorado P, Alvarez M, Llerena A: Relation between CYP2D6 phenotype and genotype and personality in healthy volunteers. Pharmacogenomics, 2008, 9, 833–840.
Haduch A, Bromek E, Daniel WA: The effect of psychotropic drugs on cytochrome P450 2D (CYP2D) in rat brain. Eur J Pharmacol, 2011, 651, 51–58.
Haduch A, Bromek E, Sadakierska-Chudy A, Wójcikowski J, Daniel WA: The catalytic competence of cytochrome P450 in the synthesis of serotonin from 5-methoxytryptamine in the brain: an in vitro study. Pharmacol Res, 2013, 67, 53–59.
Haduch A, Bromek E, Wójcikowski J, Gołembiowska K, Daniel WA: Involvement of cytochrome P450 (CYP) in melatonin-serotonin transformation in the brain. The 11th World Congress of Biological Psychiatry, 23–27 June, Kyoto, Japan, 2013, P–18–013.
Hansson T, von Bahr C, Marklund M, Svensson JO, Ingelman-Sundberg M, Lundström J: Different regiospecificity in the hydroxylation of the antidepressant desmethylimipramine between rat brain and liver. Pharmacol Toxicol, 1992, 71, 416–419.
Hedlund E, Wyss A, Kainu T, Backlund M, Köhler C, Pelto-Huikko M, Gustafsson JÅ, Warner M: Cytochrome P4502D4 in the brain: Specific neuronal regulation by clozapine and toluene. Mol Pharmacol, 1996, 50, 342–350.
Hiroi T, Imaoka S, Funae Y: Dopamine formation from tyramine by CYP2D6. Biochem Biophys Res Commun, 1998, 249, 838–843.
Hiroi T, Kishimoto W, Chow T, Imaoka S, Igarashi T, Funae Y: Progesterone oxidation by cytochrome P450 2D isoforms in the brain. Endocrinology, 2001, 142, 3901–3908.
Kirchheiner J, Seeringer A, Godoy A, Ohmle B, Maier C, Beschoner P, Sim EJ, Viviani R: CYP2D6 in the brain: genotype effects on resting brain perfusion. Mol Psychiatr, 2011, 16, 333–341.
Kishimoto W, Hiroi T, Shiraishi M, Osada M, Imaoka S, Kominami S, Igarashi T, Funae Y: Cytochrome P450 2D catalyze steroid 21-hydroxylation in the brain. Endocrinology, 2004, 145, 699–705.
Mann A, Miksys S, Lee A, Mash DC, Tyndale RF: Induction of the drug metabolizing enzyme CYP2D in monkey brain by chronic nicotine treatment. Neuropharmacology, 2008, 55, 1147–1155.
Miksys S, Rao Y, Hoffmann E, Mash DC, Tyndale RF: Regional and cellular expression of CYP2D6 in human brain: higher levels in alcoholics. J Neurochem, 2002, 82, 1376–1387.
Miksys S, Rao Y, Sellers EM, Kwan M, Mendis D, Tyndale RF: Regional and cellular distribution of CYP2D subfamily members in rat brain. Xenobiotica, 2000, 30, 547–564.
Miksys S, Tyndale RF: Cytochrome P450-mediated drug metabolism in the brain. J Psychiatry Neurosci, 2013, 38, 152–163.
Patel S, Dulluc J, Geffard M: Comparison of serotonin and 5-methoxytryptamine immunoreactivity in rat raphe nuclei. Histochemistry, 1986, 85, 259–263.
Pinna G, Costa E, Guidotti A: Fluoxetine and norfluoxetine stereospecifically and selectively increase brain neurosteriod content at doses that are inactive on 5-HT reuptake. Psychopharmacology, 2006, 186, 362–372.
Schyman P, Usharani D, Wang Y, Shaik S: Brain chemistry: how does P450 catalyze the O-demethylation reaction of 5-methoxytryptamine to yield serotonin? J Phys Chem B, 2010, 114, 7078–7089.
Singh S, Singh K, Patel DK, Singh C, Nath C, Singh VK, Singh RK, Singh MP: The expression of CYP2D22, an ortholog of human CYP2D6, in mouse striatum and its modulation in 1-methyl 4-phenyl-1,2,3,6-tetrahydro-pyridine-induced Parkinson’s disease phenotype and nicotine-mediated neuroprotection. Rejuvenation Res, 2009, 12, 185–197.
Srivastava G, Dixit A, Yadav S, Patel DK, Prakash O, Singh MP: Resveratrol potentiates cytochrome P450 2 d22-mediated neuroprotection in maneb- and paraquat-induced parkinsonism in the mouse. Free Radic Biol Med, 2012, 52, 1294–1306.
Strobel HW, Thompson CM, Antonovic L. Cytochromes P450 in brain: function and significance. Curr Drug Me-tab, 2001, 2, 199–214.
Ströhle A, Pasini A, Romeo E, Hermann B, Spalletta G, di Michele F, Holsboer F, Rupprecht R: Fluoxetine decreases concentrations of 3 α, 5 α-tetrahydrodeoxy corticosterone (THDOC) in major depression. J Psychiatr Res, 2000, 34, 183–186.
Thompson CM, Capdevila JH, Strobel HW: Recombinant cytochrome P450 2D18 metabolism of dopamine and arachidonic acid. J Pharmacol Exp Ther, 2000, 294, 1120–1130.
Uzunova V, Sheline Y, Davis JM, Rasmusson A, Uzunov DP, Costa E, Guidotti A: Increase in the cerebrospinal fluid content of neurosteroids in patients with unipolar major depression who are receiving fluoxetine or fluvoxamine. Proc Natl Acad Sci USA, 1998, 95, 3239–3244.
Voirol P, Jonzier-Perey M, Porchet F, Reymond MJ, Janzer RC, Bouras C, Strobel HW et al.: Cytochrome P-450 activities in human and rat brain microsomes. Brain Res, 2000, 855, 235–243.
Warner M, Gustafsson JĹ: Effect of ethanol on cytochrome P450 in the rat brain. Proc Natl Acad Sci USA, 1994, 91, 1019–1023.
Yu AM, Idle JR, Byrd LG, Krausz KW, Küpfer A, Gonzalez FJ: Regeneration of serotonin from 5-methoxytryptamine by polymorphic human CYP2D6. Pharmacogenetics, 2003, 13, 173–181.
Yue J, Miksys S, Hoffmann E, Tyndale RF: Chronic nicotine treatment induces rat CYP2D in the brain but not in the liver: an investigation of induction and time course. J Psychiatry Neurosci, 2008, 33, 54–63.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Haduch, A., Bromek, E. & Daniel, W.A. Role of brain cytochrome P450 (CYP2D) in the metabolism of monoaminergic neurotransmitters. Pharmacol. Rep 65, 1519–1528 (2013). https://doi.org/10.1016/S1734-1140(13)71513-5
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1016/S1734-1140(13)71513-5