Peripheral and central inhibitors of catechol-O-methyl transferase: effects on liver and brain COMT activity and L-DOPA metabolism.
Inhibitors of the enzyme catechol-O-methyl transferase (COMT) may be useful adjuncts to L-DOPA in the treatment of Parkinson's disease as they offer the possibility of increasing the availability of the amino acid. It is unknown whether a COMT inhibitor which penetrates the blood-brain barrier is preferable to one restricted to extra-cerebral inhibition. We measured liver and brain COMT activity two hours following administration of two COMT inhibitors: entacapone (ENT), mainly peripherally acting, and dinitrocatechol (DNC), peripheral and central acting. As expected, the full spectrum inhibitor DNC (30 mg/kg) induced a near total inhibition of liver and brain COMT activity. Unexpectedly, however, ENT, at 30 mg/kg, produced the same degree of liver and brain COMT inhibition as DNC; using 10mg/kg, ENT still inhibited both liver and brain COMT activity by 80%. Only at 2.5 and 5 mg/kg did ENT achieve a differential inhibition of liver (80% inhibition) versus brain (10-30% inhibition) COMT activity. In a second series of experiments, we administered ENT (2.5, 10, and 30 mg/kg) and DNC (30 mg/kg) to rats and monitored extracellular striatal dopamine and dopamine metabolite levels with cerebral microdialysis both under basal conditions and following L-DOPA/carbidopa administration. No compound modified basal striatal levels of dopamine. ENT at 30 mg/kg (but not 2.5 or 10 mg), as well as DNC, decreased striatal levels of the methylated dopamine metabolite homovanillic acid (HVA). When L-DOPA/carbidopa was administered, dopamine formation was greatest and HVA formation least in animals pretreated with DNC and 30 mg/kg ENT (but not 2.5 or 10 mg/kg ENT). The finding that ENT at doses relatively specific for peripheral enzyme inhibition did not promote dopamine or inhibit HVA formation is most likely due to the 20% residual liver COMT activity present when the inhibitor was used at less than full doses. Our data indicate that DNC and ENT both inhibit striatal HVA formation and increase dopamine formation from exogenously administered L-DOPA. The dopamine promoting effect of ENT is only present, however, at doses which inhibit central as well as peripheral COMT activity.
Brannan
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T
Department of Neurology, Mount Sinai School of Medicine, New York, NY, USA.
Prikhojan
A
A
Yahr
M D
MD
D015102:3,4-Dihydroxyphenylacetic Acid / Q000737:chemistry / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000201:enzymology* / Q000378:metabolism; D002394:Catechol O-Methyltransferase / Q000737:chemistry / Q000378:metabolism; D065098:Catechol O-Methyltransferase Inhibitors; D002396:Catechols / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D004298:Dopamine / Q000031:analogs & derivatives / Q000737:chemistry / Q000378:metabolism; D006719:Homovanillic Acid / Q000737:chemistry / Q000378:metabolism; D007980:Levodopa / Q000378:metabolism* / Q000494:pharmacology; D008099:Liver / Q000201:enzymology* / Q000378:metabolism; D008297:Male; D009570:Nitriles; D051381:Rats; D017207:Rats, Sprague-Dawley
D065098:Catechol O-Methyltransferase Inhibitors; D002396:Catechols; D009570:Nitriles; D015102:3,4-Dihydroxyphenylacetic Acid; D007980:Levodopa; C071192:entacapone; D002394:Catechol O-Methyltransferase; C034221:catechol; D004298:Dopamine; D006719:Homovanillic Acid