Alterations of the redox state, pentose pathway and glutathione metabolism in an acute porphyria model. their impact on heme pathway
A classical acute porphyria model in rats consists of combined treatment with 2-allyl-2-isopropylacetamide (AIA) and 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC). The present work describes the effects of this treatment on the pentose phosphate (PP) pathway, glutahione metabolism and redox state...
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2013
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| Acceso en línea: | https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_15353702_v238_n2_p133_Faut http://hdl.handle.net/20.500.12110/paper_15353702_v238_n2_p133_Faut |
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paper:paper_15353702_v238_n2_p133_Faut2023-06-08T16:20:06Z Alterations of the redox state, pentose pathway and glutathione metabolism in an acute porphyria model. their impact on heme pathway Glucose-6-phosphate dehydrogenase Glutathione metabolism Pentose phosphate pathway Porphyria Rat liver Reactive oxygen species 5 aminolevulinate synthase glucose glucose 6 phosphate dehydrogenase glutathione glutathione disulfide glutathione peroxidase glutathione reductase glutathione transferase heme phosphogluconate dehydrogenase pyridine nucleotide reactive oxygen metabolite acute intermittent porphyria animal experiment animal model animal tissue article blood sampling controlled study DNA damage enzyme linked immunosorbent assay female glutathione metabolism nonhuman oxidation reduction state oxidative stress pentose phosphate cycle protein determination rat spectrophotometry urinalysis Allylisopropylacetamide Animals Disease Models, Animal Glucose Glucosephosphate Dehydrogenase Glutathione Glutathione Disulfide Glutathione Peroxidase Glutathione Reductase Glutathione Transferase Heme Liver NADP Oxidation-Reduction Oxidative Stress Pentose Phosphate Pathway Porphyria, Acute Intermittent Pyridines Rats Reactive Oxygen Species A classical acute porphyria model in rats consists of combined treatment with 2-allyl-2-isopropylacetamide (AIA) and 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC). The present work describes the effects of this treatment on the pentose phosphate (PP) pathway, glutahione metabolism and redox state and how they contribute to alter the glucose pool of hepatocytes and modulate porphyria, in Wistar rat livers. Our approach is based on the fact that glucose is a repressor of 5-aminolevulinic synthase (ALA-S), the rate-limiting enzyme of the heme pathway, and treatment with AIA/DCC causes oxidative stress. Different doses of the xenobiotcs were used. The results show that AIA (500 mg/kg body weight [BW])/ DDC (50 mg/kg [BW]) treatment increased glutathione peroxidase (GPx) activity by 46%, decreased both glutathione reductase (GR) and glutathione S-transferase (GST) activity by 69% and 52%, respectively, and reduced by 51% reduced glutathione (GSH) and increased by 100% glutathione disulfide (GSSG) concentrations, therefore lowering by four-fold the GSH/GSSG ratio. The activity of glucose-6-phosphate dehydrogenase (G6PD), the rate-limiting enzyme of PP-pathway, was increased by 129% as well as that of 6-phosphogluconate dehydrogenase. NADPH and the NADPH/NADP+ ratio were increased by 14% and 28%, respectively. These effects could be attributed to the generation of reactive oxygen species (ROS) elicited by the porphyrinogenic treatment, shown by enhanced DNA damage and ROS production. G6PD stimulation would decrease hepatic glucose concentrations and consequently exacerbate the porphyria. A decrease in glucose could stimulate ALA-S and this would add to the effect of drug-induced heme depletion. Since the key role of GST is to inactivate toxic compounds, the drastic fall in its activity together with the accumulation of ALA would account for the symptoms of this hepatic disease model. The present findings show the high metabolic interplay between pathways and constitute a relevant contribution to achieve a better treatment of acute human porphyria. © 2013 by the Society for Experimental Biology and Medicine. 2013 https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_15353702_v238_n2_p133_Faut http://hdl.handle.net/20.500.12110/paper_15353702_v238_n2_p133_Faut |
| institution |
Universidad de Buenos Aires |
| institution_str |
I-28 |
| repository_str |
R-134 |
| collection |
Biblioteca Digital - Facultad de Ciencias Exactas y Naturales (UBA) |
| topic |
Glucose-6-phosphate dehydrogenase Glutathione metabolism Pentose phosphate pathway Porphyria Rat liver Reactive oxygen species 5 aminolevulinate synthase glucose glucose 6 phosphate dehydrogenase glutathione glutathione disulfide glutathione peroxidase glutathione reductase glutathione transferase heme phosphogluconate dehydrogenase pyridine nucleotide reactive oxygen metabolite acute intermittent porphyria animal experiment animal model animal tissue article blood sampling controlled study DNA damage enzyme linked immunosorbent assay female glutathione metabolism nonhuman oxidation reduction state oxidative stress pentose phosphate cycle protein determination rat spectrophotometry urinalysis Allylisopropylacetamide Animals Disease Models, Animal Glucose Glucosephosphate Dehydrogenase Glutathione Glutathione Disulfide Glutathione Peroxidase Glutathione Reductase Glutathione Transferase Heme Liver NADP Oxidation-Reduction Oxidative Stress Pentose Phosphate Pathway Porphyria, Acute Intermittent Pyridines Rats Reactive Oxygen Species |
| spellingShingle |
Glucose-6-phosphate dehydrogenase Glutathione metabolism Pentose phosphate pathway Porphyria Rat liver Reactive oxygen species 5 aminolevulinate synthase glucose glucose 6 phosphate dehydrogenase glutathione glutathione disulfide glutathione peroxidase glutathione reductase glutathione transferase heme phosphogluconate dehydrogenase pyridine nucleotide reactive oxygen metabolite acute intermittent porphyria animal experiment animal model animal tissue article blood sampling controlled study DNA damage enzyme linked immunosorbent assay female glutathione metabolism nonhuman oxidation reduction state oxidative stress pentose phosphate cycle protein determination rat spectrophotometry urinalysis Allylisopropylacetamide Animals Disease Models, Animal Glucose Glucosephosphate Dehydrogenase Glutathione Glutathione Disulfide Glutathione Peroxidase Glutathione Reductase Glutathione Transferase Heme Liver NADP Oxidation-Reduction Oxidative Stress Pentose Phosphate Pathway Porphyria, Acute Intermittent Pyridines Rats Reactive Oxygen Species Alterations of the redox state, pentose pathway and glutathione metabolism in an acute porphyria model. their impact on heme pathway |
| topic_facet |
Glucose-6-phosphate dehydrogenase Glutathione metabolism Pentose phosphate pathway Porphyria Rat liver Reactive oxygen species 5 aminolevulinate synthase glucose glucose 6 phosphate dehydrogenase glutathione glutathione disulfide glutathione peroxidase glutathione reductase glutathione transferase heme phosphogluconate dehydrogenase pyridine nucleotide reactive oxygen metabolite acute intermittent porphyria animal experiment animal model animal tissue article blood sampling controlled study DNA damage enzyme linked immunosorbent assay female glutathione metabolism nonhuman oxidation reduction state oxidative stress pentose phosphate cycle protein determination rat spectrophotometry urinalysis Allylisopropylacetamide Animals Disease Models, Animal Glucose Glucosephosphate Dehydrogenase Glutathione Glutathione Disulfide Glutathione Peroxidase Glutathione Reductase Glutathione Transferase Heme Liver NADP Oxidation-Reduction Oxidative Stress Pentose Phosphate Pathway Porphyria, Acute Intermittent Pyridines Rats Reactive Oxygen Species |
| description |
A classical acute porphyria model in rats consists of combined treatment with 2-allyl-2-isopropylacetamide (AIA) and 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC). The present work describes the effects of this treatment on the pentose phosphate (PP) pathway, glutahione metabolism and redox state and how they contribute to alter the glucose pool of hepatocytes and modulate porphyria, in Wistar rat livers. Our approach is based on the fact that glucose is a repressor of 5-aminolevulinic synthase (ALA-S), the rate-limiting enzyme of the heme pathway, and treatment with AIA/DCC causes oxidative stress. Different doses of the xenobiotcs were used. The results show that AIA (500 mg/kg body weight [BW])/ DDC (50 mg/kg [BW]) treatment increased glutathione peroxidase (GPx) activity by 46%, decreased both glutathione reductase (GR) and glutathione S-transferase (GST) activity by 69% and 52%, respectively, and reduced by 51% reduced glutathione (GSH) and increased by 100% glutathione disulfide (GSSG) concentrations, therefore lowering by four-fold the GSH/GSSG ratio. The activity of glucose-6-phosphate dehydrogenase (G6PD), the rate-limiting enzyme of PP-pathway, was increased by 129% as well as that of 6-phosphogluconate dehydrogenase. NADPH and the NADPH/NADP+ ratio were increased by 14% and 28%, respectively. These effects could be attributed to the generation of reactive oxygen species (ROS) elicited by the porphyrinogenic treatment, shown by enhanced DNA damage and ROS production. G6PD stimulation would decrease hepatic glucose concentrations and consequently exacerbate the porphyria. A decrease in glucose could stimulate ALA-S and this would add to the effect of drug-induced heme depletion. Since the key role of GST is to inactivate toxic compounds, the drastic fall in its activity together with the accumulation of ALA would account for the symptoms of this hepatic disease model. The present findings show the high metabolic interplay between pathways and constitute a relevant contribution to achieve a better treatment of acute human porphyria. © 2013 by the Society for Experimental Biology and Medicine. |
| title |
Alterations of the redox state, pentose pathway and glutathione metabolism in an acute porphyria model. their impact on heme pathway |
| title_short |
Alterations of the redox state, pentose pathway and glutathione metabolism in an acute porphyria model. their impact on heme pathway |
| title_full |
Alterations of the redox state, pentose pathway and glutathione metabolism in an acute porphyria model. their impact on heme pathway |
| title_fullStr |
Alterations of the redox state, pentose pathway and glutathione metabolism in an acute porphyria model. their impact on heme pathway |
| title_full_unstemmed |
Alterations of the redox state, pentose pathway and glutathione metabolism in an acute porphyria model. their impact on heme pathway |
| title_sort |
alterations of the redox state, pentose pathway and glutathione metabolism in an acute porphyria model. their impact on heme pathway |
| publishDate |
2013 |
| url |
https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_15353702_v238_n2_p133_Faut http://hdl.handle.net/20.500.12110/paper_15353702_v238_n2_p133_Faut |
| _version_ |
1768543005130620928 |