Metal-induced hormesis requires cPKC-dependent glucose transport and lowered respiration.
Previously, cytotoxicity studies using an 3-(4,5 dimethylthiazol-2-yl)-2,5 diphenyl tetrazolium bromide (MTT)-based in vitro toxicity assay found that low concentrations of mercuric, cadmium and cupric chloride (0.7, 1 and 3 pM, respectively) induced hormesis in McCoy cells after 24 h exposure. An investigation of the biochemical events required for the induction of this phenomenon revealed that hormesis was dependent on two simultaneous but independent events, namely, an 11-15% conventional protein kinase C (cPKC)-dependent increase in glucose uptake and a protein synthesis-dependent 19-23% drop in mitochondrial respiration. The inhibition of either event was sufficient to abolish hormesis for all three metal toxicants. Furthermore, an investigation of the energy status of cells prior to and during hormesis revealed an oscillating level of ATP production found to be in phase with mitochondrial respiration, independent of cPKC-activated glucose transport and found to coincide with a 16-20% drop in AMP-activated protein kinase activity. These findings suggest that hormesis is not a form of energy compensation but is most likely a reductive burst where an increase in glucose uptake together with a simultaneous reduction in oxygen consumption results in a significant increase in reduction equivalents, which may then be utilized by cells to counteract the effects of oxidative stress induced by heavy metal toxicants.
Damelin
L H
LH
Department of Molecular and Cell Biology, University of Witwatersrand, Johannesburg, South Africa.
Alexander
J J
JJ
D000249:Adenosine Monophosphate / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000378:metabolism*; D000818:Animals; D018929:Cell Culture Techniques; D019069:Cell Respiration / Q000187:drug effects; D004396:Coloring Agents / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D005947:Glucose / Q000493:pharmacokinetics*; D019216:Metals, Heavy / Q000633:toxicity*; D051379:Mice; D008928:Mitochondria / Q000502:physiology; D018384:Oxidative Stress; D010101:Oxygen Consumption; D011493:Protein Kinase C / Q000378:metabolism*; D013778:Tetrazolium Salts / Q000633:toxicity*; D013844:Thiazoles / Q000633:toxicity*; D018675:Toxicity Tests
D004396:Coloring Agents; D019216:Metals, Heavy; D013778:Tetrazolium Salts; D013844:Thiazoles; D000249:Adenosine Monophosphate; D000255:Adenosine Triphosphate; D011493:Protein Kinase C; C022616:thiazolyl blue; D005947:Glucose