PT - JOURNAL ARTICLE AU - Jing Lin AU - John R. Cashman TI - N-Oxygenation of Phenethylamine to the <em>trans</em>-Oxime by Adult Human Liver Flavin-Containing Monooxygenase and Retroreduction of Phenethylamine Hydroxylamine by Human Liver Microsomes DP - 1997 Sep 01 TA - Journal of Pharmacology and Experimental Therapeutics PG - 1269--1279 VI - 282 IP - 3 4099 - http://jpet.aspetjournals.org/content/282/3/1269.short 4100 - http://jpet.aspetjournals.org/content/282/3/1269.full SO - J Pharmacol Exp Ther1997 Sep 01; 282 AB - The biogenic amine phenethylamine has been shown to be N-oxygenated by human flavin-containing monooxygenase (FMO) (form 3) and human liver microsomes and, to a much lesser extent, N-oxygenated by porcine liver FMO1 and porcine liver microsomes but not by rabbit FMO2. Adult human liver microsomes catalyze the NADPH-dependent N-oxygenation of phenethylamine to the corresponding trans-oxime through the intermediacy of phenethyl hydroxylamine. In addition totrans-oxime formation, phenethyl hydroxylamine is retroreduced to phenethylamine in the presence of human or porcine liver microsomes. Studies on the biochemical mechanism of N-oxygenation suggested that trans-oxime formation was dependent on the human FMO (form 3) and that retroreduction was stimulated by superoxide and dependent on a cytochrome P-450 system. These conclusions are based on studies examining the effects of incubation conditions on phenethylamine N-oxygenation and the effect of reactive oxygen species on phenethyl hydroxylamine retroreduction, respectively. The pharmacological activity of synthetic phenethyl hydroxylamine and phenethyl oxime with a number of biogenic amine receptors and transporters was examined in vitro. In all cases examined, the affinity of phenethyl hydroxylamine and the corresponding oxime for a biogenic transporter or receptors was very poor. The results suggest that the biogenic amine phenethylamine is efficiently sequentially N-oxygenated in the presence of human liver microsomes or cDNA-expressed FMO (form 3) to phenethyl hydroxylamine and then to oximes that are pharmacologically inactive and serve to terminate biological activity. N-Oxygenation of phenethylamine to the corresponding trans-oxime is a detoxication process that abrogates pharmacological activity. The American Society for Pharmacology and Experimental Therapeutics