Free radical pathways in the in vitro hepatic metabolism of phenelzine

PR Ortiz de Montellano and MD Watanabe

The in vitro metabolism of phenelzine (2-phenylethylhydrazine) by phenobarbital-pretreated rat liver microsomes yields ethylbenzene, 2- phenylethanol, 2-phenylacetaldehyde, benzaldehyde, benzylalcohol, and toluene as metabolites. Isotopic studies demonstrate that the oxygen atom of 2-phenylethanol derives from molecular oxygen and that this alcohol is not produced by reduction of 2-phenylacetaldehyde. The rates of destruction of cytochrome P-450, accumulation of spin-trapped 2- phenylethyl radicals, and formation of ethylbenzene and 2-phenylethanol are the same for [1,1-2H]-2-phenylethylhydrazine as for the undeuterated substrate. Small primary isotope effects are observed, however, for the formation of 2-phenylacetaldehyde (kH/kD greater than 1) and benzaldehyde (kH/kD less than 1). Synthetic 2- phenylethylhydroperoxide is converted by liver microsomes to the same alcohol and aldehyde metabolites. The results indicate that the metabolism of phenelzine by rat liver microsomes proceeds primarily via the 2-phenylethyl radical.

Volume 31, Issue 2, pp. 213-219, 02/01/1987
Copyright © 1987 by American Society for Pharmacology and Experimental Therapeutics