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NEUROPHARMACOLOGY

The Relative Contribution of Monoamine Oxidase and Cytochrome P450 Isozymes to the Metabolic Deamination of the Trace Amine Tryptamine

Laboratory of Metabolism, National Cancer Institute, National Institutes of Health, Bethesda, Maryland (C.P.G., A.M.Y., K.W.K, J.C., F.J.G.); Department of Basic Pharmaceutical Sciences, School of Pharmacy, West Virginia University, Morgantown, West Virginia (R.L.H.); Department of Clinical Pharmacology, University of Bern, Bern, Switzerland (A.K.); and Institute for Cancer Research and Molecular Biology, Norwegian University of Science and Technology, Trondheim, Norway (J.R.I.)

Tryptamine is a trace amine in mammalian central nervous system that interacts with the trace amine TA₂ receptor and is now thought to function as a neurotransmitter or neuromodulator. It had been reported that deamination of tryptamine to tryptophol was mediated by CYP2D6, a cytochrome P450 that is expressed in human brain, suggesting that tryptamine may be an endogenous substrate for this polymorphic enzyme. We were unable to confirm this report and have reinvestigated tryptamine metabolism in human liver microsomes (HLM) and in microsomes expressing recombinant human cytochrome P450 and monoamine oxidase (MAO) isozymes. Tryptamine was oxidized to indole-3-acetaldehyde by HLM and recombinant human MAO-A in the absence of NADPH, and indole-3-acetaldehyde was further reduced to tryptophol by aldehyde reductase in HLM in the presence of NADPH. Steady-state kinetic parameters were estimated for each reaction step by HLM and MAO-A. The CYP2D6 substrates bufuralol and debrisoquine showed strong inhibition of both tryptophol production from tryptamine in HLM and the formation of indole-3-acetaldehyde from tryptamine catalyzed by recombinant MAO-A. Anti-CYP2D6 monoclonal antibody did not inhibit these reactions. Pargyline, a nonselective MAO inhibitor, did not show cross inhibition to debrisoquine 4-hydroxylation and dextromethorphan O-demethylation by HLM and recombinant CYP2D6 enzyme. This is the first unequivocal report of the selective conversion of tryptamine to tryptophol by MAO-A. CYP2D6 does not contribute to this reaction.

Address correspondence to: Dr. Frank J. Gonzalez Laboratory of Metabolism National Cancer Institute National Institutes of Health Bldg., 37, Rm. 3E24 Bethesda, MD 20892. E-mail: fjgonz{at}helix.nih.gov

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