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OtherDRUG METABOLISM AND DISPOSITION

N-Oxygenation of Phenethylamine to the trans-Oxime by Adult Human Liver Flavin-Containing Monooxygenase and Retroreduction of Phenethylamine Hydroxylamine by Human Liver Microsomes

Jing Lin and John R. Cashman
Journal of Pharmacology and Experimental Therapeutics September 1997, 282 (3) 1269-1279;
Jing Lin
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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 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.

Footnotes

  • Send reprint requests to: John R. Cashman, Ph.D., Seattle Biomedical Research Institute, 4 Nickerson Street, Suite 200, Seattle, WA 98108. E-mail:jcashman{at}sbri.org

  • ↵1 This work was supported by National Institutes of Health Grants GM36426 and DA00269. Data in table 9 were obtained through the National Institute on Drug Abuse Cocaine Treatment Discovery Program, Contracts DA38302 and DA38303.

  • ↵2 A full description of the human FMO3-MBP construct has been submitted for publication (Brunelle et al., Drug Metab Dispos., in press).

  • ↵3 Restriction length polymorphism and oligonucleotide-sequencing studies showed that codon 158 encoded either amino acids Glu or Lys at approximately equal allele frequencies for the Caucasian populations examined (E. Treacy, R. Youil, S, Forest and M. Knight, unpublished observations).

  • Abbreviations:
    FMO
    flavin-containing monooxygenase
    MAO
    monoamine oxidase
    CYP
    cytochrome P-450
    MI
    metabolic inhibitory
    MS (FAB)
    mass spectrometry (fast atom bombardment)
    TEA
    triethylamine
    FMO3-MBP
    flavin-containing monooxygenase (form 3)-maltose binding protein
    HPLC
    high pressure liquid chromatography
    DETAPAC
    diethylenetriaminepentaacetic acid
    SOD
    superoxide dismutase
    5-HT
    serotonin
    CHO
    Chinese hamster ovary
    • Received January 14, 1997.
    • Accepted May 16, 1997.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics
Vol. 282, Issue 3
1 Sep 1997
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OtherDRUG METABOLISM AND DISPOSITION

N-Oxygenation of Phenethylamine to the trans-Oxime by Adult Human Liver Flavin-Containing Monooxygenase and Retroreduction of Phenethylamine Hydroxylamine by Human Liver Microsomes

Jing Lin and John R. Cashman
Journal of Pharmacology and Experimental Therapeutics September 1, 1997, 282 (3) 1269-1279;

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OtherDRUG METABOLISM AND DISPOSITION

N-Oxygenation of Phenethylamine to the trans-Oxime by Adult Human Liver Flavin-Containing Monooxygenase and Retroreduction of Phenethylamine Hydroxylamine by Human Liver Microsomes

Jing Lin and John R. Cashman
Journal of Pharmacology and Experimental Therapeutics September 1, 1997, 282 (3) 1269-1279;
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