Document Detail

Apoptotic and necrotic effects of hexanedione derivatives on the human neuroblastoma line SK-N-SH.
MedLine Citation:
PMID:  17229511     Owner:  NLM     Status:  MEDLINE    
The potential cytotoxicity of two hexanedione food additives (2,3 and 3,4 isomers) was evaluated in comparison with the neurotoxic hexane metabolite 2,5-hexanedione in the human SK-N-SH neuroblastoma line using the MTT assay to indicate mitochondrial dehydrogenase activity and flow cytometry to monitor the cell cycle over 48 h. The IC(50)s of the 2,3-hexanedione (3.3+/-0.1 mM) and 3,4-hexanedione (3.5+/-0.1 mM), indicated that the sensitivity of the cells was approximately seven-fold greater to these toxins compared with the 2,5 derivative (IC(50) of 22.4+/-0.2 mM). Comparison between the respective IC(50)s of the 2,3-hexanedione and 3,4-hexanedione revealed no difference between the two isomers in terms of their effects on MTT turnover. With flow cytometry analysis, all three hexanediones showed increases in apoptosis within their respective concentration ranges of toxicity shown previously by MTT. In the presence of 2,5-hexanedione, between 8.5 and 17 mM concentrations, there was a significant increase in apoptotic nucleoids which was accompanied by a significant fall in the percentage of nucleoids in the G0/G1 phase (72.4+/-0.3-45.3+/-0.6%,), and a rise in the numbers of cells in the G2/M phase. This is likely to indicate growth arrest at cell cycle G2/M checkpoint in response to toxin damage. G2/M accumulation was also shown with 3,4 and 2,3 HD, which was maximal at much lower concentrations (approximately 4 and 3mM, respectively). Arrest at G1 and G2/M phase is indicative of inhibition of the cell cycle at the stages of DNA replication and chromosome segregation, respectively. It was also apparent that flow cytometry, rather than the MTT assay, did distinguish between the effects of the alpha-diketones 2,3-hexanedione and 3,4-hexanedione on the cell cycle. At a concentration of 5.8mM 3,4-hexanedione, the percentage of apoptotic nucleoids was 10.9+/-0.8% whilst apoptosis induced by 3,4-hexanedione had already reached a maximal level of 60.4+/-0.5%. In summary, flow cytometry indicated that the 3,4-hexanedione derivative was more toxic than its 2,3 isomer and that both food additives caused interruption in the neuroblastoma cell cycle and further investigation may be required to assess if these alpha-diketones present in diets pose any possible risks to human health.
Thomas R Zilz; Helen R Griffiths; Michael D Coleman
Publication Detail:
Type:  Comparative Study; Journal Article; Research Support, Non-U.S. Gov't     Date:  2006-12-10
Journal Detail:
Title:  Toxicology     Volume:  231     ISSN:  0300-483X     ISO Abbreviation:  Toxicology     Publication Date:  2007 Mar 
Date Detail:
Created Date:  2007-02-27     Completed Date:  2007-04-17     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  0361055     Medline TA:  Toxicology     Country:  Ireland    
Other Details:
Languages:  eng     Pagination:  210-4     Citation Subset:  IM    
School of Life and Health Sciences, Aston University, Birmingham, UK.
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MeSH Terms
Apoptosis / drug effects*
Cell Cycle / drug effects
Cell Line, Tumor
Cell Survival / drug effects
Dose-Response Relationship, Drug
Flow Cytometry
Food Additives / toxicity*
Formazans / metabolism
Hexanones / toxicity*
Necrosis / chemically induced*
Neurons / drug effects*,  metabolism,  pathology
Neurotoxins / toxicity
Tetrazolium Salts / metabolism
Reg. No./Substance:
0/Food Additives; 0/Formazans; 0/Hexanones; 0/Neurotoxins; 0/Tetrazolium Salts; 110-13-4/2,5-hexanedione; 23305-68-2/MTT formazan; 3848-24-6/2,3-hexanedione

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

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