title: Elevation of rat brain tyrosine levels by phenelzine is mediated by its active metabolite β-phenylethylidenehydrazine.
abstract: Phenelzine, a non-selective irreversible inhibitor of monoamine oxidase (MAO), has been used in the treatment of depression and anxiety disorders for several decades. It is a unique inhibitor of MAO as it is also a substrate for MAO, with one of the metabolites being β-phenylethylidenehydrazine (PEH), and it also inhibits several transaminases (e.g. GABA transaminase) in the brain when administered i.p. to rats. Administration of either phenelzine or PEH to rats has been reported to produce dramatic increases in rat brain levels of GABA and alanine while reducing levels of glutamine; these effects are abolished for phenelzine, but not for PEH, when the animals are pre-treated with another MAO inhibitor, suggesting that they are mediated by the MAO-catalyzed formation of PEH from phenelzine. In the present report, we have found that phenelzine and E- and Z-geometric isomers of PEH significantly increased rat whole brain concentrations of L-tyrosine. In a time-response study, acute administration of phenelzine, E-PEH and Z-PEH (30 mg/kg i.p.) elevated rat whole brain L-tyrosine levels at 3 and 6h following injection, reaching approximately 265-305% of vehicle-treated controls at 3h. To determine whether the effect on L-tyrosine is MAO-dependent, animals were pre-treated with the non-selective MAO inhibitor tranylcypromine (1mg/kg i.p.) prior to administration of phenelzine, racemic PEH or vehicle controls. This pre-treatment reversed the effects of phenelzine, but not of PEH, on brain L-tyrosine levels, suggesting that the tyrosine-elevating property of phenelzine is largely the result of its active metabolite PEH. These results are discussed in relation to possible therapeutic applications of these drugs.
authors.affiliation: Neurochemical Research Unit, Department of Psychiatry, University of Alberta, Edmonton, Canada. Electronic address: dmitriym@ualberta.ca.
authors.forename: Dmitriy
authors.initials: D
authors.lastname: Matveychuk
authors.affiliation: Neurochemical Research Unit, Department of Psychiatry, University of Alberta, Edmonton, Canada. Electronic address: emerson_arcoverde@yahoo.com.br.
authors.forename: Emerson
authors.initials: E
authors.lastname: Nunes
authors.affiliation: Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Canada. Electronic address: nasirullah@hotmail.com.
authors.forename: Nasir
authors.initials: N
authors.lastname: Ullah
authors.affiliation: Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Canada. Electronic address: aldawsar@ualberta.ca.
authors.forename: Fahad S
authors.initials: FS
authors.lastname: Aldawsari
authors.affiliation: Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Canada. Electronic address: velazque@ualberta.ca.
authors.forename: Carlos A
authors.initials: CA
authors.lastname: Velázquez-Martínez
authors.affiliation: Neurochemical Research Unit, Department of Psychiatry, University of Alberta, Edmonton, Canada; Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Canada. Electronic address: glen.baker@ualberta.ca.
authors.forename: Glen B
authors.initials: GB
authors.lastname: Baker
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D001921:Brain / Q000187:drug effects*; D055664:Electrochemical Techniques; D006834:Hydrazines / Q000494:pharmacology*; D008689:Methacrylates; D008996:Monoamine Oxidase Inhibitors / Q000494:pharmacology*; D010624:Phenelzine / Q000494:pharmacology*; D051381:Rats; D013997:Time Factors; D014443:Tyrosine / Q000378:metabolism*
chemical_list: D006834:Hydrazines; D008689:Methacrylates; D008996:Monoamine Oxidase Inhibitors; C084776:pheniprazine; D014443:Tyrosine; D010624:Phenelzine; C032802:hydroxypropyl methacrylate
keywords: Depression; Neurodegenerative disorders; Phenelzine; l-Tyrosine; β-Phenylethylidenehydrazine