Comparison of cytotoxicity of a quaternary pyridinium metabolite of haloperidol (HP+) with neurotoxin N-methyl-4-phenylpyridinium (MPP+) towards cultured dopaminergic neuroblastoma cells.
Haloperidol has recently been found to be metabolized to its pyridinium ion (HP+). This conversion of haloperidol to HP+ appears to be similar to the activation of the dopaminergic neurotoxin N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) to N-methyl-4-phenyl pyridinium ion (MPP+). MPP+ is responsible for the damage of striatal dopaminergic neurons induced by MPTP in humans and animals. It seemed sensible to investigate whether or not HP+ might be toxic towards dopaminergic neurons and perhaps associated with some of the residual moto-function side effects of haloperidol. We therefore investigated the neurotoxicity of HP+ toward cultured human dopamine neuroblastoma cells (SH-SY5Y) and compared it with that of MPP+. HP+ reduced the viability as measured by MTT and [3H]thymidine incorporation methods in SH-SY5Y cells. Cell membrane integrity is reduced by the treatment of HP+ as measured by intracellular LDH levels. The toxicity was concentration and time dependent. Interestingly, HP+ appeared to be more toxic than MPP+ towards the SH-SY5Y cells in early phase in cultures. The toxicity of MPP+ appear to be progressive and subsequently become more than HP+ with prolonged cultivation. In contrary to MPP+, the toxic effect of HP+ towards a dopamine transporter transfected SK-N-MC cell line is not different from its wild type. This indicates that dopamine uptake system is probably not involved in the cytotoxicity caused by HP+.
Fang
J
J
Department of Psychiatry, University of Saskatchewan, Saskatoon, Canada.
Zuo
D
D
Yu
P H
PH
D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / Q000378:metabolism; D015655:1-Methyl-4-phenylpyridinium / Q000378:metabolism* / Q000633:toxicity*; D000818:Animals; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D006220:Haloperidol / Q000378:metabolism* / Q000633:toxicity*; D020267:MPTP Poisoning; D009447:Neuroblastoma; D009498:Neurotoxins / Q000494:pharmacology; D010300:Parkinson Disease; D013997:Time Factors
D009498:Neurotoxins; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D006220:Haloperidol; D015655:1-Methyl-4-phenylpyridinium