Differences in the disposition and toxicity of 1-methyl-4-phenylpyridinium in cultured rat and mouse astrocytes.
Species difference in the susceptibility to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) was investigated in cultured rat and mouse astrocytes, where 1-methyl-4-phenylpyridinium (MPP+), the toxic mediator of MPTP, is formed. Type A monoamine oxidase (MAO) predominated in both rat and mouse astrocytes, while its activity was slightly higher in mouse cells compared to rat cells; MAO-B activity, on the other hand, was significantly lower in mouse astrocytes than in rat astrocytes. Because both types of MAO have been reported to make similar contributions to MPP+ production in astrocytes, their total activity was examined and results indicated that there was no significant difference between these two species. In addition, MPP+ caused a dose-dependent loss of cell viability as judged by the amount of lactate dehydrogenase released into the incubation medium. The toxicity of MPP+ on astrocytes started to be seen after a 2 day incubation period. Mouse astrocytes were more vulnerable to MPP+ than rat astrocytes. The threshold values for MPP+ toxicity in mouse and rat cultures were 10 microM and 70 microM, respectively. After addition of [3H] MPP+ to the medium, intracellular [3H] MPP+ was found to increase in both cultures. Mouse astrocytes accumulated more MPP+ than rat astrocytes (150 pmol/mg protein vs. 65 pmol/mg protein). When astrocytes were allowed to accumulate [3H] MPP+ and then incubated in fresh medium not containing [3H] MPP+, intracellular levels of [3H] MPP+ in both cells rapidly declined (110 pmol/protein in mouse vs. 40 pmol/mg protein in rat of MPP+ been released).(ABSTRACT TRUNCATED AT 250 WORDS)
Tsai
M J
MJ
Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan, Republic of China.
Lee
E H
EH
D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / Q000493:pharmacokinetics*; D015655:1-Methyl-4-phenylpyridinium / Q000493:pharmacokinetics* / Q000633:toxicity*; D000818:Animals; D001253:Astrocytes / Q000187:drug effects* / Q000378:metabolism*; D002462:Cell Membrane / Q000378:metabolism; D002478:Cells, Cultured; D004351:Drug Resistance; D020267:MPTP Poisoning; D051379:Mice; D008995:Monoamine Oxidase / Q000378:metabolism; D051381:Rats; D013045:Species Specificity; D014018:Tissue Distribution
D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D008995:Monoamine Oxidase; D015655:1-Methyl-4-phenylpyridinium