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Abstract:

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.

Registro:

Documento: Artículo
Título:Alterations of the redox state, pentose pathway and glutathione metabolism in an acute porphyria model. their impact on heme pathway
Autor:Faut, M.; Paiz, A.; de Viale, L.C.S.M.; Mazzetti, M.B.
Filiación:Laboratorio de Disturbios Metabólicos por Xenobióticos, Salud Humana y Medio Ambiente, Departamento de Química Biológica, Universidad de Buenos Aires, Ciudad Universitaria, Pab. II, 4to Piso, Ciudad Autónoma de Buenos Aires, C1428EGA, Argentina
Palabras clave: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
Año:2013
Volumen:238
Número:2
Página de inicio:133
Página de fin:143
DOI: http://dx.doi.org/10.1177/1535370212473702
Título revista:Experimental Biology and Medicine
Título revista abreviado:Exp. Biol. Med.
ISSN:15353702
CODEN:EBMMB
CAS:5 aminolevulinate synthase, 9037-14-3; glucose, 50-99-7, 84778-64-3; glucose 6 phosphate dehydrogenase, 37259-83-9, 9001-40-5; glutathione, 70-18-8; glutathione disulfide, 27025-41-8; glutathione peroxidase, 9013-66-5; glutathione reductase, 9001-48-3; glutathione transferase, 50812-37-8; heme, 14875-96-8; phosphogluconate dehydrogenase, 9001-82-5; 3,5-diethoxycarbonyl-1,4-dihydrocollidine; Allylisopropylacetamide, 299-78-5; Glucose, 50-99-7; Glucosephosphate Dehydrogenase, 1.1.1.49; Glutathione, 70-18-8; Glutathione Disulfide, 27025-41-8; Glutathione Peroxidase, 1.11.1.9; Glutathione Reductase, 1.8.1.7; Glutathione Transferase, 2.5.1.18; Heme, 14875-96-8; NADP, 53-59-8; Pyridines; Reactive Oxygen Species
Registro:https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_15353702_v238_n2_p133_Faut

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Citas:

---------- APA ----------
Faut, M., Paiz, A., de Viale, L.C.S.M. & Mazzetti, M.B. (2013) . Alterations of the redox state, pentose pathway and glutathione metabolism in an acute porphyria model. their impact on heme pathway. Experimental Biology and Medicine, 238(2), 133-143.
http://dx.doi.org/10.1177/1535370212473702
---------- CHICAGO ----------
Faut, M., Paiz, A., de Viale, L.C.S.M., Mazzetti, M.B. "Alterations of the redox state, pentose pathway and glutathione metabolism in an acute porphyria model. their impact on heme pathway" . Experimental Biology and Medicine 238, no. 2 (2013) : 133-143.
http://dx.doi.org/10.1177/1535370212473702
---------- MLA ----------
Faut, M., Paiz, A., de Viale, L.C.S.M., Mazzetti, M.B. "Alterations of the redox state, pentose pathway and glutathione metabolism in an acute porphyria model. their impact on heme pathway" . Experimental Biology and Medicine, vol. 238, no. 2, 2013, pp. 133-143.
http://dx.doi.org/10.1177/1535370212473702
---------- VANCOUVER ----------
Faut, M., Paiz, A., de Viale, L.C.S.M., Mazzetti, M.B. Alterations of the redox state, pentose pathway and glutathione metabolism in an acute porphyria model. their impact on heme pathway. Exp. Biol. Med. 2013;238(2):133-143.
http://dx.doi.org/10.1177/1535370212473702