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Hoffmann, R. A wiki for the life sciences where authorship matters. Nature Genetics (2008)

Prolongation of G1 and S phase in C-6 glioma cells treated with maple syrup urine disease metabolits. Morphologic and cell cycle studies.

Metabolites accumulating in maple syrup urine disease, a disease attributable to an inborn error in the catabolism of branched-chain amino acids, were administered to rat C-6 glioma cells maintained in monolayer culture in order to study the morphologic and cell kinetic changes caused by these metabolites. Computer analysis of fraction-labeled mitoses in combination with flow microfluorometric analysis was used to analyze the effects of these metabolites on the cell cycle. The maple syrup urine disease metabolites, i.e., L-leucine, L-isoleucine, and L-valine and their corresponding ketoacids caused a prolongation of the G1 and S phases, when administered in combination at concentrations corresponding to approximately the highest recorded plasma levels in patients with the disease (1 x level). This effect was not reversible. Ketoleucine (alpha-ketoisocarproic acid or AKICA) alone, the compound that accumulates in maple syrup urine disease and that has previously been shown to be the most important metabolite associated with it, caused marked prolongation of the G1 and, to a lesser extent, the S phase at concentrations of 200 mg. per 100 ml. Return of the AKICA-treated growth-arrested cells to a standard medium caused complete reversal of grwoth inhibition. Consistent fine structural changes were found in cells treated with AKICA at concentrations of 300 mg. per 100 ml. or with the combined maple syrup urine disease metabolites at a 2 x level. These included marked cell process elongation and the appearance of numerous bundles of cytoplasmic filaments.[1]


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