caa a22 4500 445852984 CHVBK 20180317145419.0 cr unu---uuuuu 170323e20110901xx s 000 0 eng 10.1007/s00204-010-0633-6 doi (NATIONALLICENCE)springer-10.1007/s00204-010-0633-6 Cadmium chloride inhibits lactate gluconeogenesis in isolated human renal proximal tubules: a cellular metabolomic approach with 13C-NMR [Elektronische Daten] [Hassan Faiz, Agnès Conjard-Duplany, Michelle Boghossian, Guy Martin, Gabriel Baverel, Bernard Ferrier] As part of a study on cadmium nephrotoxicity, we studied the effect of cadmium chloride (CdCl2) in isolated human renal proximal tubules metabolizing the physiological substrate lactate. Dose-effect experiments showed that 10-500μM CdCl2 reduced lactate removal, glucose production and the cellular levels of ATP, coenzyme A, acetyl-coenzyme A and of reduced glutathione in a dose-dependent manner. After incubation with 5mM l-[1-13C]-, or l-[2-13C]-, or l-[3-13C] lactate or 5mM l-lactate plus 25mM NaH13CO3 as substrates, substrate utilization and product formation were measured by both enzymatic and carbon 13 NMR methods. Combination of enzymatic and NMR measurements with a mathematical model of lactate metabolism previously validated showed that 100μM CdCl2 caused an inhibition of flux through lactate dehydrogenase and alanine aminotransferase and through the entire gluconeogenic pathway; fluxes were diminished by 19% (lactate dehydrogenase), 28% (alanine aminotransferase), 28% (pyruvate carboxylase), 42% (phosphoenolpyruvate carboxykinase), and 52% (glucose-6-phosphatase). Such effects occurred without altering the oxidation of the lactate carbons or fluxes through enzymes of the tricarboxylic acid cycle despite a large fall of the cellular ATP level, a marker of the energy status and of the viability of the renal cells. These results that were observed at clinically relevant tissue concentrations of cadmium provide a biochemical basis for a better understanding of the cellular mechanism of cadmium-induced renal proximal tubulopathy in humans chronically exposed to cadmium. Springer-Verlag, 2010 Nephrotoxicity nationallicence Cadmium nationallicence Metabolism nationallicence Lactate nationallicence Human nationallicence Gluconeogenesis nationallicence Faiz Hassan Faculté de Médecine Laennec, INSERM Unit # 820 (Metabolomics and Metabolic Diseases), Rue G. Paradin, 69372, Lyon Cedex 08, France aut Conjard-Duplany Agnès Faculté de Médecine Laennec, INSERM Unit # 820 (Metabolomics and Metabolic Diseases), Rue G. Paradin, 69372, Lyon Cedex 08, France aut Boghossian Michelle Faculté de Médecine Laennec, INSERM Unit # 820 (Metabolomics and Metabolic Diseases), Rue G. Paradin, 69372, Lyon Cedex 08, France aut Martin Guy Faculté de Médecine Laennec, INSERM Unit # 820 (Metabolomics and Metabolic Diseases), Rue G. Paradin, 69372, Lyon Cedex 08, France aut Baverel Gabriel Metabolys Inc, Faculté de Médecine Laennec, Université de Lyon, Lyon, France aut Ferrier Bernard Faculté de Médecine Laennec, INSERM Unit # 820 (Metabolomics and Metabolic Diseases), Rue G. Paradin, 69372, Lyon Cedex 08, France aut Archives of Toxicology Springer-Verlag 85/9(2011-09-01), 1067-1077 0340-5761 85:9<1067 2011 85 204 https://doi.org/10.1007/s00204-010-0633-6 text/html Onlinezugriff via DOI 1 research-article jats NATIONALLICENCE 856 40 https://doi.org/10.1007/s00204-010-0633-6 text/html Onlinezugriff via DOI NATIONALLICENCE 700 1- Faiz Hassan Faculté de Médecine Laennec, INSERM Unit # 820 (Metabolomics and Metabolic Diseases), Rue G. Paradin, 69372, Lyon Cedex 08, France aut NATIONALLICENCE 700 1- Conjard-Duplany Agnès Faculté de Médecine Laennec, INSERM Unit # 820 (Metabolomics and Metabolic Diseases), Rue G. Paradin, 69372, Lyon Cedex 08, France aut NATIONALLICENCE 700 1- Boghossian Michelle Faculté de Médecine Laennec, INSERM Unit # 820 (Metabolomics and Metabolic Diseases), Rue G. Paradin, 69372, Lyon Cedex 08, France aut NATIONALLICENCE 700 1- Martin Guy Faculté de Médecine Laennec, INSERM Unit # 820 (Metabolomics and Metabolic Diseases), Rue G. Paradin, 69372, Lyon Cedex 08, France aut NATIONALLICENCE 700 1- Baverel Gabriel Metabolys Inc, Faculté de Médecine Laennec, Université de Lyon, Lyon, France aut NATIONALLICENCE 700 1- Ferrier Bernard Faculté de Médecine Laennec, INSERM Unit # 820 (Metabolomics and Metabolic Diseases), Rue G. Paradin, 69372, Lyon Cedex 08, France aut NATIONALLICENCE 773 0- Archives of Toxicology Springer-Verlag 85/9(2011-09-01), 1067-1077 0340-5761 85:9<1067 2011 85 204 Metadata rights reserved Springer special CC-BY-NC licence nationallicence BK010053 XK010053 XK010000 NATIONALLICENCE NATIONALLICENCE NL-springer