Department of Neurology, University of Tennessee Health Science Center, Memphis, Tennessee, U.S.A.
The introduction of levodopa therapy for Parkinson's disease (PD), initially by Birkmayer et al. (1) in 1961, by Barbeau et al. (2) in 1962, and in its ultimately successful form by Cotzias et al. (3) in 1967, still represents the defining landmark in the treatment of PD. This dramatic advance was preceded by methodical basic laboratory research in the late 1950s and early 1960s, which formed a groundwork documenting the presence of striatal dopamine deficiency in PD (4-8) and paved the road for the application of this knowledge in the clinical arena.
These developments took place against a broader backdrop in which both the role of catecholamines and their metabolic pathways in the body and brain were being unraveled (9). As part of this panorama, Axelrod in 1957 first suggested that one of the metabolic pathways for catecholamines might be via O-methylation (9-11), and in the same year, Shaw et al. (12) proposed that catechol-O-methyltransferase (COMT) might be important in the inactivation of dihydroxyphenylalanine (DOPA) and dopamine. By 1964, the metabolic pathways for DOPA and dopamine had been delineated and the enzymes involved were identified. Aromatic amino acid decarboxylase (AAAD) and COMT were identified as being responsible for converting DOPA to dopamine and 3-O-methyldopa (3-OMD), respectively, whereas monoamine oxidase (MAO) and COMT were documented to convert dopamine to 3,4-dihydroxyphenylacetic acid (DOPAC) and 3-methoxytyramine (3-MT), respectively. As early as 1964, it was suggested that agents inhibiting COMT might potentiate the effects of DOPA (13).
COMT is present throughout the body, with highest concentrations in the liver, kidneys, gastrointestinal tract, spleen, and lungs (14-17). It is also present in the brain, where it resides primarily in non-neuronal cells such as glia. There is little COMT in neurons and none has been identified in nigrostriatal dopaminergic neurons (18). COMT exists in a soluble form within the cytoplasm in most tissues, but membrane-bound COMT accounts for 70% of the total enzyme present in the brain (19). A number of substrates are acted upon by COMT, including catecholamines, such as epinephrine, norepinephrine, and dopamine, and their hydroxylated metabolites, but all known substrates have a catechol configuration (11). COMT mediates the transfer of a methyl group from S-adenosylmethionine to a hydroxyl group on the catechol molecule. Its actions, especially in the peripheral structures such as intestinal mucosa, seem to be primarily directed toward protecting the body by inactivating biologically active or toxic catechol compounds (11,18-20). Both levodopa and dopamine are examples of such biologically active compounds.
The COMT gene has been identified on chromosome 22 (21). Two alleles, one thermostable with high activity and one thermolabile with low activity, have been identified, with a three- to four-fold difference in activity (19,22). The clinical relevance of this polymorphism is uncertain.
Recognition of the bioavailability of orally administered levodopa in the treatment of PD, with perhaps only 1% of it actually reaching the brain because of extensive peripheral metabolism by both AAAD and COMT (18,23), fueled the search for drugs that might inhibit the two enzymes and improve levodopa's therapeutic efficacy. This led to the introduction of two inhibitors of AAAD, carbidopa and benser-azide, as adjunctive agents administered concomitantly with levodopa to PD patients (24,25). Administering levodopa in conjunction with an AAAD inhibitor remains the standard today. However, the use of these agents only expands the amount of levodopa reaching the brain to an estimated 10% of an administered dose, primarily because blocking AAAD simply shunts levodopa into the COMT metabolic pathway, with an increased peripheral formation of 3-OMD (23).
Was this article helpful?