Steps in the synthetic pathway of epinephrine and norepinephrine.
It is important to make a clear distinction between neuronal and vesicular transport. Neuronal transport occurs from the junctional extracellular fluid (biophase) across the cell membrane of the neuron and into the neuronal cytosol. Vesicular transport is from the neuronal cytosol across the membrane of the vesicle and into the vesicle. Although these two systems readily transport both norepinephrine and epinephrine, certain drugs will selectively inhibit one or the other transport system.
The second most important mechanism for removing norepinephrine from the synapse is the escape of neuronally released norepinephrine into the general circulation and its metabolism in the liver. The liver has two enzymes that perform this function: catechol-O-methyltransferase (COMT) and MAO.
COMT is a specific enzyme, accepting only catechols as substrates. A catechol is a substance with two adja cent hydroxyl groups on an unsaturated six-member ring. The end result of the action of COMT is the O-methylation of the meta-hydroxyl group on the catechol nucleus. Figure 9.5 illustrates the action of COMT on norepinephrine or epinephrine. This reaction reduces the biological activity of norepinephrine or epinephrine at least 100-fold.
MAO is a much less discriminating enzyme in that it will catalyze the removal of an amine group from a variety of substrates. The action of MAO on norepineph-rine and epinephrine also is indicated in Figure 9.5. The list of its substrates is very large, including endogenous substances (norepinephrine, epinephrine, dopamine, tyramine, 5-hydroxy-tryptamine) and many drugs that are amines. At least in the brain, two separate forms of MAO have been described: MAO type A and MAO type B. The two types are differentiated on the basis of substrate and inhibitor specificity.
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