Dopamine transporter and catechol-O-methyltransferase activities are required for the toxicity of 1-(3',4'-dihydroxybenzyl)-1,2,3, 4-tetrahydroisoquinoline.
1-(3',4'-Dihydroxybenzyl)-1,2,3,4-tetrahydroisoquinoline [3', 4'DHBnTIQ (1)] is an endogenous parkinsonism-inducing substance. It is taken up into dopaminergic neurons via the dopamine transporter, inhibits mitochondrial respiration, and induces parkinsonism in mice. We synthesized four derivatives [aromatized, N-methylated, N-methyl-aromatized, and O-methylated (2-5, respectively)] and studied the cellular uptake and cytotoxicity of 1-5, as well as the metabolism of 1. All except the O-methyl derivative (5) were specifically taken up by the dopamine transporter, but 1 was taken up most efficiently. Relative to 1, oxidation reduced v(max), N-methylation markedly increased K(m), and O-methylation eliminated the uptake activity. The cytotoxicity of 1-5 was examined in a mesencephalic cell primary culture. Compound 1 reduced cell viability by nearly 80% at 100 microM, but the other compounds had little or no effect on cell viability. In vivo and in vitro studies revealed that 1 was O-methylated by soluble catechol-O-methyltransferase (COMT). Aromatization and N-methylation of 1 were not observed. We found that dopamine transporter inhibitors and a COMT inhibitor each blocked the cytotoxicity of 1, indicating that uptake and O-methylation are both necessary for neurotoxicity. Thus, we consider that 1 is taken up into dopaminergic neurons via the dopamine transporter and then converted by COMT to 5, which has cytotoxic and parkinsonism-inducing activities.
Kawai
H
H
Graduate School of Pharmaceutical Sciences, University of Tokyo, Tokyo 113-0033, Japan.
Kotake
Y
Y
Ohta
S
S
D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism; D002394:Catechol O-Methyltransferase / Q000378:metabolism*; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism; D008297:Male; D008636:Mesencephalon / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D009498:Neurotoxins / Q000378:metabolism* / Q000633:toxicity; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D013574:Synaptosomes / Q000187:drug effects / Q000378:metabolism; D014213:Tretoquinol / Q000031:analogs & derivatives* / Q000378:metabolism* / Q000633:toxicity
C110419:1-(3',4'-dihydroxybenzyl)-1,2,3,4-tetrahydroisoquinoline; D002352:Carrier Proteins; D009498:Neurotoxins; D002394:Catechol O-Methyltransferase; D014213:Tretoquinol; D004298:Dopamine