Effects of zinc on SN56 cholinergic neuroblastoma cells.
Zinc is a trace element necessary for proper development and function of brain cells. However, excessive accumulation of zinc exerts several cytotoxic effects in the brain. The aim of this work was to see whether cytotoxic effects of zinc are quantitatively correlated with changes in acetyl-CoA metabolism. The zinc levels up to 0.20 mmol/L caused concentration-dependent inhibition of pyruvate dehydrogenase (PDH) activity that correlated with the increase in trypan blue-positive fraction and the decrease in cultured cell number (r = 0.96, p = 0.0001). Chronic exposure of cells to 0.15 mmol/L zinc decreased choline acetyltransferase and aconitase activities, cytoplasmic acetyl-CoA and whole cell ATP level by 38%, 57%, 35%, and 62%, respectively but caused no change in mitochondrial acetyl-CoA level and activities of other enzymes of glycolytic and tricarboxylic acid cycle. dl-alpha-lipoamide when added simultaneously with zinc to cultured cells or their homogenates attenuated its chronic or acute suppressive effects. In homogenates of chronically Zn-treated cells, lipoamide overcame PDH but not aconitase inhibition. Presented data indicate that acute-transient elevation of zinc caused reversible inhibition of PDH, aconitase activities and acetyl-CoA metabolism, which when prolonged could lead to irreversible enzyme inactivation yielding decrease in cell viability and secondary suppression of their cholinergic phenotype.
Ronowska
Anna
A
Department of Laboratory Medicine, Medical University of Gdańsk, Poland.
Gul-Hinc
Sylwia
S
Bielarczyk
Hanna
H
Pawełczyk
Tadeusz
T
Szutowicz
Andrzej
A
D000105:Acetyl Coenzyme A / Q000187:drug effects* / Q000378:metabolism; D000109:Acetylcholine / Q000096:biosynthesis*; D000154:Aconitate Hydratase / Q000037:antagonists & inhibitors / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D045744:Cell Line, Tumor; D002795:Choline O-Acetyltransferase / Q000037:antagonists & inhibitors / Q000378:metabolism; D002952:Citric Acid Cycle / Q000187:drug effects / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D004734:Energy Metabolism / Q000187:drug effects* / Q000502:physiology; D004789:Enzyme Activation / Q000187:drug effects / Q000502:physiology; D004791:Enzyme Inhibitors / Q000633:toxicity; D006019:Glycolysis / Q000187:drug effects / Q000502:physiology; D051379:Mice; D009410:Nerve Degeneration / Q000139:chemically induced* / Q000378:metabolism / Q000503:physiopathology; D009447:Neuroblastoma; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D009498:Neurotoxins / Q000633:toxicity; D011768:Pyruvate Dehydrogenase Complex / Q000187:drug effects / Q000378:metabolism; D008063:Thioctic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D015032:Zinc / Q000633:toxicity*
D004791:Enzyme Inhibitors; D009498:Neurotoxins; D011768:Pyruvate Dehydrogenase Complex; D000105:Acetyl Coenzyme A; D008063:Thioctic Acid; D000255:Adenosine Triphosphate; C013091:lipoamide; D002795:Choline O-Acetyltransferase; D000154:Aconitate Hydratase; D015032:Zinc; D000109:Acetylcholine