Inhibition of six copper-containing amine oxidases by the antidepressant drug tranylcypromine.
Potential inhibitory effects of the clinically utilized monoamine oxidase inhibitor tranylcypromine (TCP) on mammalian, plant, bacterial, and fungal copper-containing amine oxidases have been examined. The following enzymes have been investigated: human kidney diamine oxidase (HKAO), bovine plasma amine oxidase (BPAO), equine plasma amine oxidase (EPAO), pea seedling amine oxidase (PSAO), Arthrobacter globiformis amine oxidase (AGAO), and Pichia pastoris lysyl oxidase (PPLO). Only BPAO, EPAO, and AGAO were found to lose significant levels of activity when incubated with varying amounts of TCP. Inhibition of BPAO was completely reversible, with dialysis restoring full activity. TCP inhibition of AGAO was also found to be ultimately reversible; however, dialysis did not remove all bound compounds. Chemical displacement with either substrate or a substrate analogue successfully removed all bound TCP, indicating that this compound has a high affinity for the active site of AGAO. The notable lack of TCP inhibition on HKAO argues against the inhibition of diamine oxidase as a potential source for some of the deleterious side effects occurring in patients treated with this antidepressant. The marked differences observed in behavior among these enzymes speaks to the importance of intrinsic structural differences between the active sites of copper amine oxidases (CAO) which affect reactivity with a given inhibitor.
Shepard
Eric M
EM
Department of Chemistry and Biochemistry, Montana State University, Bozeman, MT 59717, USA.
Heggem
Heather
H
Juda
Gregory A
GA
Dooley
David M
DM
D006631:Amine Oxidase (Copper-Containing) / Q000037:antagonists & inhibitors*; D000928:Antidepressive Agents / Q000494:pharmacology*; D001596:Benzylamines / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D010084:Oxidation-Reduction; D010659:Phenylhydrazines / Q000494:pharmacology; D013057:Spectrum Analysis; D014191:Tranylcypromine / Q000494:pharmacology*
D000928:Antidepressive Agents; D001596:Benzylamines; D004791:Enzyme Inhibitors; D010659:Phenylhydrazines; C030299:phenylhydrazine; D014191:Tranylcypromine; C030796:benzylamine; D006631:Amine Oxidase (Copper-Containing)