Cytotoxicity of 17 tetrahydroisoquinoline derivatives in SH-SY5Y human neuroblastoma cells is related to mitochondrial NADH-ubiquinone oxidoreductase inhibition.
Since the first report that 1-methyl-4-phenyl-l,2,3,6-tetrahydropyridine induces parkinsonism, various kinds of low-molecular-weight neurotoxins, such as tetrahydroisoquinoline derivatives, have been identified as possible Parkinson's disease-inducing substances. In the present study, we measured four parameters of 17 tetrahydroisoquinoline derivatives, i.e., cytotoxicity in SH-SY5Y human neuroblastoma cells, inhibitory activity towards mitochondrial NADH-ubiquinone oxidoreductase (complex I), affinity for dopamine transporter, and 1-butanol-H2O partition coefficient (as an index of lipophilicity). Six of the derivatives showed comparatively strong inhibitory activity towards complex I (IC50 values<100 microM) and five of them were cytotoxic to SH-SY5Y cells (TC50 values<200 microM). Some of these compounds are endogenous. We found good correlations between cytotoxicity and complex I inhibitory activity, but not between cytotoxicity and affinity for dopamine transporter. Since cytotoxicity to SH-SY5Y neuroblastoma cells was related to inhibitory activity towards mitochondrial complex I, complex I inhibition is likely to be involved, at least in part, in the mechanism of TIQ derivative-induced cell death. Uptake of most of these compounds seems to be dependent on lipophilicity, rather than active transport via dopamine transporter.
Kotake
Yaichiro
Y
Graduate School of Biomedical Sciences, Center for Quantum Life Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima 734-8553, Japan. yaichiro@hiroshima-u.ac.jp
Sekiya
Yoko
Y
Okuda
Katsuhiro
K
Ohta
Shigeru
S
D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000633:toxicity*; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000473:pathology; D002470:Cell Survival / Q000187:drug effects; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D004298:Dopamine / Q000378:metabolism; D050483:Dopamine Plasma Membrane Transport Proteins / Q000378:metabolism; D042967:Electron Transport Complex I / Q000037:antagonists & inhibitors*; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000633:toxicity*; D006801:Humans; D008055:Lipids / Q000737:chemistry; D008928:Mitochondria / Q000187:drug effects / Q000201:enzymology*; D009447:Neuroblastoma / Q000188:drug therapy* / Q000473:pathology; D010302:Parkinson Disease, Secondary / Q000139:chemically induced; D013329:Structure-Activity Relationship; D044005:Tetrahydroisoquinolines / Q000138:chemical synthesis / Q000633:toxicity*
D000970:Antineoplastic Agents; D050483:Dopamine Plasma Membrane Transport Proteins; D004791:Enzyme Inhibitors; D008055:Lipids; D044005:Tetrahydroisoquinolines; D042967:Electron Transport Complex I; D004298:Dopamine