J. Lin, J. Cashman
Sep 1, 1997
Citations
1
Influential Citations
36
Citations
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Journal
The Journal of pharmacology and experimental therapeutics
Abstract
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 to trans-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.