N-oxygenation of phenethylamine to the trans-oxime by adult human liver flavin-containing monooxygenase and retroreduction of phenethylamine hydroxylamine by human liver microsomes.
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.
Lin
J
J
Seattle Biomedical Research Institute, Washington 98108, USA.
Cashman
J R
JR
D000328:Adult; D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism; D050483:Dopamine Plasma Membrane Transport Proteins; D006801:Humans; D006898:Hydroxylamines / Q000378:metabolism; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D008862:Microsomes, Liver / Q000378:metabolism*; D009419:Nerve Tissue Proteins; D010091:Oximes / Q000378:metabolism*; D010105:Oxygenases / Q000502:physiology*; D010627:Phenethylamines / Q000378:metabolism*; D011817:Rabbits; D013552:Swine
D002352:Carrier Proteins; D050483:Dopamine Plasma Membrane Transport Proteins; D006898:Hydroxylamines; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; D010091:Oximes; D010627:Phenethylamines; C029261:phenethylamine; D010105:Oxygenases; C020066:dimethylaniline monooxygenase (N-oxide forming)