How Do Drugs Damage Neurons? It’s Radical! 0/8
Oxidation of Dopamine
Once dopamine1 is released into the synaptic space, its actions are terminated in two ways. First, it is transported back into the dopamine terminal by “uptake pumps” (Figure 2), which are special proteins that act as transporters2. Second, dopamine is oxidized by oxygen (O2), which is available after it diffuses from blood capillaries into spaces surrounding the neurons. The dopamine can be oxidized by two different processes. Normally, oxidation3 of dopamine by O2 is catalyzed by enzymes4 called monoamine oxidases4. These oxidases are found in the mitochondria within the nerve terminal. Dopamine is a monoamine; it contains one amine (NH2) group. Its structure is shown in Figure 3. So, once inside the terminal, the monoamine oxidase helps O2 remove an electron (associated with the H) from the CH2 group nearest the NH2 on dopamine. The loss of the e- from the CH2 group removes the amine group (NH2) as well (the H combines with NH2 to form NH2 or ammonia). Now, one O atom can bind to fill its octet with a double bond to CH. This general reaction for the oxidation of dopamine is shown in Figure 3.
Molecular oxygen (O2) contains 12 electrons in the outer orbital, but 2 of these electrons are unpaired. Because of the 2 unpaired electrons in the outer orbital, O2 likes to accept a single electron from compounds such as dopamine or metals in the body (e.g., iron, copper); it is a good oxidizing agent for this reason. Thus, the dopamine becomes oxidized and the O2 becomes reduced. In other words, O2 acts as an oxidizing agent5 to oxidize dopamine; dopamine acts as a reducing agent6 to reduce O2. This oxidative reaction results in the formation of a metabolite7called dihydroxyphenylacetaldehyde (DPA), an inactive neurotransmitter metabolite. The other O atom combines with H2O to form hydrogen peroxide8 (H2O2), which is converted back to water with the help of another enzyme called catalase.
1 a neurotransmitter stored in vesicles of nerve terminals; it is a monoamine that is easily oxidized. This neurotransmitter is contained in neuron pathways important in brain stimulation, addiction and control of movement.
2 a protein that usually exists within a membrane to transport a compound (either large or charged) across the membrane to the other side.
3 the donation of electrons to another atom often by removal of a H+ atom.
4 a protein that catalyzes the rate at which a reaction occurs. It binds to one of the reactants (a substrate) to cause a change in the reactant’s structure, facilitating the reaction.
5 the mitochondrial enzyme that helps O2 oxidize monoamines such as dopamine to inert products. Monoamines have one amine group (NH2) within the molecule.
6 a species that is good at gaining electrons (e.g. O2, Fe3+)
7 a species that is good at donating electrons (e.g. Fe2+)
8 usually an inactive form of a drug or other substance that is more polar (charged) than the parent compound. Drugs are metabolized by enzymes primarily in the liver.
9 formed from the reduction of the superoxide radical by superoxide dismutase, but it is not actually a radical. It is detoxified by conversion to O2 and H2O by the enzyme catalase.