Eisenhofer G, Finberg J P
Clinical Neuroscience Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland.
J Pharmacol Exp Ther. 1994 Mar;268(3):1242-51.
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.
去甲变肾上腺素（NMN）和变肾上腺素（MN）是去甲肾上腺素（NE）和肾上腺素（E）的O-甲基化代谢产物，而二羟基苯乙二醇（DHPG）是NE和E的脱氨基代谢产物。本研究比较了在大鼠中，在有或没有抑制儿茶酚-O-甲基转移酶（COMT）或单胺氧化酶（MAO）的A和B形式的情况下，在示踪剂和高剂量输注NE和E期间NMN、MN和DHPG的生成情况。动物还接受了NMN和MN的输注，以比较在有或没有MAO抑制的情况下NMN和MN的血浆清除率和溢出率。抑制COMT会增加血浆DHPG并降低血浆NMN和MN，而抑制MAO会降低血浆DHPG并增加血浆NMN和MN。MAO抑制后NMN和MN的增加反映了MAO-A对NMN和MN脱氨基作用的阻断，而非MAO-B。MAO的A形式在很大程度上也负责NE的脱氨基作用。输注的E比NE更不易脱氨基生成DHPG。高剂量输注的E比NE更有效地进行O-甲基化，而示踪剂剂量的O-甲基化情况相似。MAO抑制后NE比E更有效地进行O-甲基化。MAO抑制后血浆NMN的增加反映了NMN血浆清除率降低和NMN向血浆中溢出增加的综合作用，而血浆MN较小的增加仅归因于MN血浆清除率的降低。因此，E和MN在O-甲基化的非神经部位不会脱氨基，而NE既会进行O-甲基化也会脱氨基，并且随着NE浓度的增加，脱氨基的比例比O-甲基化的比例更大。上述结果支持NE比E更倾向于通过神经元代谢途径，但表明在非神经O-甲基化和脱氨基作用下，NE和E的代谢存在相当复杂的差异。
