No abstract

1.Unlike cell lines and primary cells in culture, precision-cut tissue slices remain metabolically differentiated for at least 24-48 h and allow to study the effect of xenobiotics during short-term and long-term incubations. 2.In this article, we illustrate the use of such an experimental model to study the nephrotoxic effects of (i) chloroacetaldehyde, a metabolite of the anticancer drug ifosfamide, (ii) of cobalt chloride, a potential leakage product of the cobalt-containing nanoparticles, and (iii) of valproate, a widely used antiepileptic drug. 3.Since all the latter test compounds, like many toxic compounds, negatively interact with cellular metabolic pathways, we also illustrate our biochemical toxicology approach in which we used not only enzymatic but also carbon 13 NMR measurements and mathematical modelling of metabolic pathways. 4.This original approach, which can be applied to any tissue, allows to predict the nephrotoxic effects of milligram amounts of test compounds very early during the research and development processes of drugs and chemicals. This approach, combined with the use of cells that retain their in vivo metabolic properties and, therefore, are predictive, reduces the risk, the time and cost of such processes.

Chloroacetaldehyde (CAA), a product of hepatic metabolism of the widely used anticancer drug ifosfamide (IFO), has been reported to decrease cancer cell proliferation. The basis of this effect is not completely known but has been attributed to a drop of cellular ATP content. Given the importance of glucose metabolism and of the 'Warburg effect' in cancer cells, we examined in the present study the ability of CAA to inhibit cancer cell proliferation by altering the glycolytic pathway. Cell proliferation, ATP content, glucose transport and metabolism as well as the activities of the main enzymes of glycolysis were determined in human breast cancer cells MCF-7 in the presence of various CAA concentrations (5-50 microm). Our results show that low CAA concentrations inhibited cell proliferation in a concentration-dependent manner. This inhibition was explained by a decrease in glucose utilization. Cellular ATP content was not reduced but even increased with 25 microm CAA. The inhibition of glucose metabolism was mainly explained by the decrease in glucose transport and hexokinase activity. The activity of glyceraldehyde-3-phosphate dehydrogenase, but not that of phosphofructokinase, was also inhibited. Glycolysis inhibition by CAA was effective in decreasing the proliferation of MCF-7 cells. Interestingly, this decrease was not due to ATP depletion; rather, it was linked to a drop of biosynthetic precursors from glycolytic intermediates. This CAA-induced inhibition of cell proliferation suggests that it might play a role in the antitumor activity of IFO.