1-Methyl-4-(2'-ethylphenyl)-1,2,3,6-tetrahydropyridine-induced toxicity in PC12 cells is enhanced by preventing glycolysis.
The effects of 1-methyl-4-(2'-ethylphenyl)-1,2,3,6-tetrahydropyridine (2'Et-MPTP), 1-methyl-4-(2'-ethylphenyl)pyridinium (2'Et-MPP+), and the classic complex 1 inhibitor, rotenone, on toxicity as well as on rates of glucose use and lactate production were studied using the pheochromocytoma PC12 cell line. PC12 cells are neoplastic in nature and have a high rate of glycolysis accompanied by a large production of lactate and a low use of glucose carbon through the Krebs cycle. 1-Methyl-4-phenylpyridinium (MPP+) and analogues such as 2'Et-MPP+ are actively accumulated by mitochondrial preparations in vitro and block NADH dehydrogenase of complex 1. This blockade results in biochemical sequelae that are ultimately cytotoxic. In this study, untreated PC12 cells used glucose and concomitantly accumulated lactate in a time-dependent manner at all concentrations of glucose studied. Treatment with 50 microM 2'Et-MPP+ or 50 nM rotenone increased both rates significantly, indicating a shift toward increased glycolysis. Cell death caused by the neurotoxins was also time and concentration dependent and markedly enhanced by glucose depletion in the medium. The increase in 2'Et-MPTP-induced toxicity in low glucose-supplemented cells was not due to an increase in pyridinium formation from the tetrahydropyridine, but rather to the lack of glucose for glycolysis. Moreover, inhibition of glycolysis with 2-deoxyglucose or iodoacetic acid also enhanced the lethality of the neurotoxins to the cells. The data in this study provide additional support to the hypothesis that 2'Et-MPP+ or related analogues act to kill cells by inhibiting mitochondrial respiration.(ABSTRACT TRUNCATED AT 250 WORDS)
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Department of Neurology, University of Medicine and Dentistry, New Jersey-Robert Wood Johnson Medical School, Piscataway 08854.
Heikkila
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Saporito
M S
MS
Philbert
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M
Geller
H M
HM
Nicklas
W J
WJ
D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000494:pharmacology; D015655:1-Methyl-4-phenylpyridinium / Q000494:pharmacology; D000818:Animals; D005947:Glucose / Q000378:metabolism; D006019:Glycolysis / Q000187:drug effects*; D007773:Lactates / Q000378:metabolism; D019344:Lactic Acid; D016716:PC12 Cells / Q000187:drug effects* / Q000378:metabolism; D012402:Rotenone / Q000494:pharmacology; D013997:Time Factors
D007773:Lactates; D012402:Rotenone; C065330:1-methyl-4-(2'-ethylphenyl)-1,2,3,6-tetrahydropyridine; D019344:Lactic Acid; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D005947:Glucose; D015655:1-Methyl-4-phenylpyridinium