Different metabolism of norepinephrine and epinephrine by catechol-O-methyltransferase and monoamine oxidase in rats.
Normetanephrine (NMN) and metanephrine (MN), are the O-methylated metabolites of norepinephrine (NE) and epinephrine (E), whereas dihydroxyphenylglycol (DHPG) is the deaminated metabolite of both NE and E. This study compared production of NMN, MN and DHPG during tracer and high-dose infusions of Ne and E in rats, with and without inhibition of catechol-O-methyltransferase (COMT) or the A and B forms of monoamine oxidase (MAO). Animals also received infusions of NMN and MN to compare plasma clearances and spillovers of NMN and MN with and without MAO inhibition. Inhibition of COMT increased plasma DHPG and decreased plasma NMN and MN, whereas inhibition of MAO decreased plasma DHPG and increased plasma NMN and MN. The increase in NMN and MN after MAO inhibition reflected blocked deamination of NMN and MN by MAO-A, but not MAO-B. The A form of MAO was also largely responsible for deamination of NE. Infused E was deaminated to DHPG less efficiently than NE. High doses of infused E were O-methylated more efficiently than NE, whereas tracer doses were O-methylated similarly. After MAO inhibition NE was O-methylated more efficiently than E. Increased plasma NMN after MAO inhibition reflected the combined effects of a decrease in the plasma clearance of NMN and an increase in the spillover of NMN into plasma, whereas the smaller increase in plasma MN was due solely to a decrease in the plasma clearance of MN. Thus, E and MN are not deaminated at extraneuronal sites of O-methylation, whereas NE is both O-methylated and deaminated with proportionally more deaminated than O-methylated as the concentration of NE increases. The above results support the preference of NE over E for neuronal pathways of metabolism, but indicate considerably more complex differences in the metabolism of NE and E by extraneuronal O-methylation and deamination.
Eisenhofer
G
G
Clinical Neuroscience Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland.
Finberg
J P
JP
D000818:Animals; D002394:Catechol O-Methyltransferase / Q000378:metabolism*; D065098:Catechol O-Methyltransferase Inhibitors; D004837:Epinephrine / Q000378:metabolism*; D007554:Isotopes; D008297:Male; D008676:Metanephrine / Q000097:blood / Q000493:pharmacokinetics; D008995:Monoamine Oxidase / Q000378:metabolism*; D008996:Monoamine Oxidase Inhibitors / Q000494:pharmacology; D009638:Norepinephrine / Q000378:metabolism*; D009647:Normetanephrine / Q000097:blood / Q000493:pharmacokinetics; D051381:Rats; D017207:Rats, Sprague-Dawley
D065098:Catechol O-Methyltransferase Inhibitors; D007554:Isotopes; D008996:Monoamine Oxidase Inhibitors; D009647:Normetanephrine; D008676:Metanephrine; D008995:Monoamine Oxidase; D002394:Catechol O-Methyltransferase; D009638:Norepinephrine; D004837:Epinephrine