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Journal article
Rotenone Stereospecifically Increases (S)-2-Hydroxyglutarate in SH-SY5Y Neuronal Cells
Chemical research in toxicology, v 28(5), pp 948-954
01 May 2015
PMID: 25800467
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Abstract
The alpha-ketoglutarate metabolite, 2-hydroxyglutratetarate (2-HG), has emerged as an important mediator in a subset of cancers and rare inherited inborn errors of metabolism. Because:of potential enantiospecific metabolism, chiral analysis is essential for determining the biochemical, impacts of altered 2-HG metabolism. We have developed a novel application of chiral liquid chromatography electron capture/atmospheric pressure chemical ionization-/mass spectrometry, which allows for the quantification of both (R)-2-HG (D-2-HG) and (S)-2-HG (L-2-HG) in human cell lines. This method avoids the need for chiral derivatization, which could potentially distort enantiomer ratios through racemization during the derivatization process. The study revealed that the pesticide rotenone (100 nM), a mitochondrial complex I inhibitor, caused a significant almost 3-fold increase in the level's of (S)-2-HG, (91.7 +/- 7.5 ng/10(6) cells) when Compared with the levels of (R)-2-HG (24.1 +/- 1.2 ng/10(6) cells) in the SH-SY5Y neuronal cells, a widely used model of human neurons. Stable isotope tracers and isotopologue analysis revealed that the increased (S)-2-HG was derived primarily from L-glutamine. Accumulation of highly toxic (S)-2-HG occurs in the brains of subjects with reduced L-2-HG dehydrogenase activity that results from mutations in the L2HGDR gene. This, suggests that the observed stereospecific increase of (S)-2-HG in neuronal cells is due to rotenone-mediated inhibition of L-2-HG dehydrogenase but not D-2-HG dehydrogenase. The high sensitivity chiral analytical methodology that has been developed in the present study can also be employed for analyzing other disruptions to 2-HG formation and metabolism such as those resulting from Mutations in the isocitrate dehydrogenase gene.
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Details
- Title
- Rotenone Stereospecifically Increases (S)-2-Hydroxyglutarate in SH-SY5Y Neuronal Cells
- Creators
- Andrew J. Worth - Univ Penn, Perelman Sch Med, Penn SRP Ctr, Philadelphia, PA 19104 USAKevin P. Gillespie - Univ Penn, Perelman Sch Med, Dept Syst Pharmacol & Translat Therapeut, Philadelphia, PA 19104 USAClementina Mesaros - Univ Penn, Perelman Sch Med, Penn SRP Ctr, Philadelphia, PA 19104 USALili Guo - Univ Penn, Perelman Sch Med, Dept Syst Pharmacol & Translat Therapeut, Philadelphia, PA 19104 USASankha S. Basu - Univ Penn, Perelman Sch Med, Ctr Excellence Environm Toxicol, Philadelphia, PA 19104 USANathaniel W. Snyder - Drexel UniversityIan A. Blair - Univ Penn, Perelman Sch Med, Penn SRP Ctr, Philadelphia, PA 19104 USA
- Publication Details
- Chemical research in toxicology, v 28(5), pp 948-954
- Publisher
- American Chemical Society; Washington, DC
- Number of pages
- 7
- Grant note
- P30ES013508; T32ES019851 / National Institutes of Health; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA T32ES019851 / NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute of Environmental Health Sciences (NIEHS)
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- A.J. Drexel Autism Institute
- Web of Science ID
- WOS:000354907500012
- Scopus ID
- 2-s2.0-84929600761
- Other Identifier
- 991019167622204721
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- Collaboration types
- Domestic collaboration
- Web of Science research areas
- Chemistry, Medicinal
- Chemistry, Multidisciplinary
- Toxicology