Dopamine transporter and catechol-O-methyltransferase activities are required for the toxicity of 1-(3 ',4 '-dihydroxybenzyl)-1,2,3,4-tetrahydroisoquinoline

Citation
H. Kawai et al., Dopamine transporter and catechol-O-methyltransferase activities are required for the toxicity of 1-(3 ',4 '-dihydroxybenzyl)-1,2,3,4-tetrahydroisoquinoline, CHEM RES T, 13(12), 2000, pp. 1294-1301
Citations number
34
Language
INGLESE
art.tipo
Article
Categorie Soggetti
Pharmacology & Toxicology
Journal title
CHEMICAL RESEARCH IN TOXICOLOGY
ISSN journal
0893-228X → ACNP
Volume
13
Issue
12
Year of publication
2000
Pages
1294 - 1301
Database
ISI
SICI code
0893-228X(200012)13:12<1294:DTACAA>2.0.ZU;2-8
Abstract
1-(3',4'-Dihydroxybenzyl)-1,2,3,4-tetrahydroisoquinoline [3',4'DHBnTIQ (1)] is an endogenous parkinsonism-inducing substance. It is taken up into dopa minergic neurons via the dopamine transporter, inhibits mitochondrial respi ration, and induces parkinsonism in mice. We synthesized four derivatives [ aromatized, N-methylated, N-methyl-aromatized, and O-methylated (2-5, respe ctively)] 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 specifi cally taken up by the dopamine transporter, but 1 was taken up most efficie ntly. Relative to 1, oxidation reduced upsilon (max), N-methylation markedl y increased K-m, and O-methylation eliminated the uptake activity. The cyto toxicity of 1-5 was examined in a mesencephalic cell. primary culture. Comp ound I reduced cell viability by nearly 80% at 100 muM, but the other compo unds had little or no effect on cell viability. In vivo and in vitro studie s revealed that I was O-methylated by soluble catechol-O-methyltransferase (COMT). Aromatization and N-methylation of 1 were not observed. We found th at dopamine transporter inhibitors and a COMT inhibitor each blocked the cy totoxicity of I, indicating that uptake and O-methylation are both necessar y for neurotoxicity. Thus, we consider that 1 is taken up into dopaminergic neurons via the dopamine transporter and then converted by COMT to 5, whic h has cytotoxic and parkinsonism-inducing activities.