The mechanism of perturbation in monoamine metabolism by L-dopa therapy: in vivo and in vitro studies.
In the cerebrospinal fluid of the patients with Parkinson's disease treated with L-DOPA, L-3-O-methyldopa was the major metabolite of administered L-DOPA. Using a dopaminergic cell model, clonal rat phenochromocytoma PC 12h cells, and by microdialysis of the rat striatum it was proved that L-3-O-methyldopa was taken up into monoamine neurons by transport system specific for aromatic L-amino acids and inhibited transport of L-DOPA and other amino acids competitively. L-3-O-Methyldopa depleted allosteric regulation of the biopterin cofactor on activity of tyrosine hydroxylase, the rate-limiting enzyme of catecholamine synthesis. Depletion of the allostery may perturb the buffer action of endogenous L-DOPA synthesis that stabilizes dopamine level in the brain. By these mechanisms L-3-O-methyldopa may reduce clinical effectiveness of administered L-DOPA and be involved in wearing-off phenomenon. L-DOPA inhibited the activity of tryptophan hydroxylase and thus serotonin synthesis, which may be related to psychiatric side-effects in the patients under L-DOPA therapy.
Department of Neurology, Nagoya University School of Medicine, Japan.
W
W
Maruyama
M
M
Naoi
A
A
Takahashi
H
H
Watanabe
Y
Y
Konagaya
K
K
Mokuno
S
S
Hasegawa
D
D
Nakahara
D000368:Aged; D000596:Amino Acids / Q000134:cerebrospinal fluid / Q000378:metabolism; D000818:Animals; D015306:Biogenic Monoamines / Q000134:cerebrospinal fluid / Q000378:metabolism*; D003342:Corpus Striatum / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D003956:Dialysis; D004298:Dopamine / Q000502:physiology; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D007700:Kinetics; D007980:Levodopa / Q000494:pharmacology* / Q000627:therapeutic use; D008297:Male; D008875:Middle Aged; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D016716:PC12 Cells; D010300:Parkinson Disease / Q000134:cerebrospinal fluid / Q000201:enzymology / Q000378:metabolism; D051381:Rats; D014365:Tryptophan Hydroxylase / Q000134:cerebrospinal fluid / Q000378:metabolism; D014443:Tyrosine / Q000031:analogs & derivatives / Q000493:pharmacokinetics; D014446:Tyrosine 3-Monooxygenase / Q000134:cerebrospinal fluid / Q000378:metabolism
D000596:Amino Acids; D015306:Biogenic Monoamines; D014443:Tyrosine; D007980:Levodopa; D014446:Tyrosine 3-Monooxygenase; D014365:Tryptophan Hydroxylase; C008404:3-methoxytyrosine; D004298:Dopamine