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Peter R. Sinclair - One of the best experts on this subject based on the ideXlab platform.
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effect of an oral iron chelator or iron deficient diets on uroporphyria in a murine model of porphyria cutanea tarda
Hepatology, 2007Co-Authors: Nadia Gorman, Judith M. Jacobs, Jacqueline F. Sinclair, Adrian Zaharia, Heidi S Trask, Juliana G Szakacs, Nicholas J Jacobs, Dominic Balestra, Peter R. SinclairAbstract:Porphyria cutanea tarda is a liver disease characterized by elevated hepatic iron and excessive production of Uroporphyrin (URO). Phlebotomy is an effective treatment that probably acts by reducing hepatic iron. Here we used Hfe(−/−) mice to compare the effects on hepatic URO accumulation of two different methods of hepatic iron depletion: iron chelation using deferiprone (L1) versus iron-deficient diets. Hfe(−/−) mice in a 129S6/SvEvTac background were fed 5-aminolevulinic acid (ALA), which results in hepatic URO accumulation, and increasing doses of L1 in the drinking water. Hepatic URO accumulation was completely prevented at low L1 doses, which partially depleted hepatic nonheme iron. By histological assessment, the decrease in hepatic URO accumulation was associated with greater depletion of iron from hepatocytes than from Kupffer cells. The L1 treatment had no effect on levels of hepatic cytochrome P4501A2 (CYP1A2). L1 also effectively decreased hepatic URO accumulation in C57BL/6 Hfe(−/−) mice treated with ALA and a CYP1A2 inducer. ALA-treated mice maintained on defined iron-deficient diets, rather than chow diets, did not develop uroporphyria, even when the animals were iron-supplemented either directly in the diet or by iron dextran injection. Conclusion: The results suggest that dietary factors other than iron are involved in the development of uroporphyria and that a modest depletion of hepatocyte iron by L1 is sufficient to prevent URO accumulation. (HEPATOLOGY 2007.)
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Effect of insulin and glucagon on accumulation of Uroporphyrin and coproporphyrin from 5-aminolevulinate in hepatocyte cultures.
Archives of biochemistry and biophysics, 2005Co-Authors: Heidi W Trask, Judith M. Jacobs, Jacqueline F. Sinclair, Nadia Gorman, Nicholas J Jacobs, Dominic Balestra, Barney E. Dwyer, Peter R. SinclairAbstract:Primary cultures of chick embryo hepatocytes have been used to study the mechanisms by which various drugs and other chemicals cause accumulation of porphyrin intermediates of the heme pathway. When these cultures are incubated with the heme precursor, 5-aminolevulinic acid (ALA), there is a major accumulation of protoporphyrin. However, in the presence of ALA, addition of insulin caused a striking increase in accumulation of Uroporphyrin I and coproporphyrin III, whereas addition of glucagon mainly caused an increase in Uroporphyrin I. Treatment with both insulin and glucagon resulted in additive increases in Uroporphyrin, but not coproporphyrin. Antioxidants abolished the Uroporphyrin I accumulation and increased coproporphyrin III. Insulin caused an increase in uptake of ALA and an increase in porphobilinogen accumulation, suggesting that the accumulation of Uroporphyrin I is due to increased flux through the heme pathway. Apparently, this increased flux could particularly affect the utilization of the intermediate hydroxymethylbilane, which would result in accumulation of Uroporphyrin I.
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Uroporphyrin accumulation in hepatoma cells expressing human or mouse cyp1a2 relation to the role of cyp1a2 in human porphyria cutanea tarda
Biochemical Pharmacology, 2003Co-Authors: Ralph C Nichols, Jacqueline F. Sinclair, Nadia Gorman, Sandra Cooper, Heidi W Trask, Timothy P Dalton, Daniel W Nebert, Peter R. SinclairAbstract:Abstract In experimental animals, CYP1A2 is absolutely required for the development of uroporphyria induced by treatment with polyhalogenated aromatic compounds or other compounds. Although the role of this CYP in clinical uroporphyria, porphyria cutanea tarda (PCT), is not clear, Cyp1a2(−/−) mice are resistant to the development of uroporphyria. Here, we compared the abilities of human and mouse CYP1A2 expressed in mouse hepatoma Hepa-1 cells to: (i) catalyze CYP1A2-dependent methoxyresorufin demethylase (MROD), and (ii) support Uroporphyrin (URO) accumulation. Both CYP1A2 orthologs were expressed at similar levels as indicated by immunodetectable CYP1A2 proteins and MROD activities. URO accumulation was increased in cultures expressing either ortholog when supplemented with 5-aminolevulinic acid, the porphyrin precursor. Cells expressing mouse CYP1A2 produced more URO than cells expressing human CYP1A2. The results indicate that human CYP1A2 can support URO accumulation in hepatoma cells and thus may play a role in human PCT.
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identification of cyp1a5 as the cyp1a enzyme mainly responsible for Uroporphyrinogen oxidation induced by ah receptor ligands in chicken liver and kidney
Drug Metabolism and Disposition, 1997Co-Authors: Peter R. Sinclair, Jacqueline F. Sinclair, Nadia Gorman, Heidi S Walton, Charis A Lee, Arleen B RifkindAbstract:Uroporphyrinogen is an intermediate of the heme biosynthetic pathway. The oxidation of Uroporphyrinogen to Uroporphyrin (UROX) has been demonstrated to be catalyzed by mammalian CYP1A2. This reaction has an important role in uroporphyria caused by halogenated aromatic compounds. Two CYP enzymes induced by Ah receptor ligands were purified recently from chick embryo liver. One, designated CYP1A5, was preferentially active in arachidonic acid epoxygenation and the other, designated CYP1A4, in 7-ethoxyresorufin deethylase (EROD) and aryl hydrocarbon hydroxylase (AHH), reactions mainly catalyzed by CYP1A1 in rodents. The amino acid sequences of both CYP1A5 and CYP1A4 are more similar to CYP1A1 than to 1A2, and neither can be classified as an ortholog of mammalian CYP1A1 or 1A2. Here we report that reconstituted purified CYP1A5 was eight times more active than CYP1A4 in catalyzing UROX. The stimulation of UROX by 3,4,3′,4′-tetrachlorobiphenyl that has been observed in microsomes was also observed with the reconstituted enzymes. Similar dose response relationships were found for induction of UROX and EROD in both chick embryo liver microsomes and in cultured chick hepatocytes, indicating coinduction of CYP1A5 and CYP1A4. UROX was induced by the Ah receptor ligand, 3-methylcholanthrene, in chicken kidney as well as liver. The findings reported here and other evidence that CYP1A4 and CYP1A5 tend to exhibit CYP1A1 and 1A2-like enzyme activites, respectively, indicate that the division of some enzyme activities among CYP1A enzymes applies to different vertebrate classes.
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Ascorbic acid deficiency in porphyria cutanea tarda
The Journal of laboratory and clinical medicine, 1997Co-Authors: Peter R. Sinclair, Jacqueline F. Sinclair, Nadia Gorman, Steven I Shedlofsky, Charles P Honsinger, Margaret R Karagas, Karl E AndersonAbstract:Porphyria cutanea tarda (PCT), the most common form of porphyria, is manifested as skin photosensitivity caused by excess hepatic production of Uroporphyrin and heptacarboxylporphyrin. In experimental animal models, ascorbic acid modulates chemically induced Uroporphyrin accumulation. The purpose of this study was to determine whether ascorbic acid is decreased in the plasma of patients with PCT. Plasma was obtained after an overnight fast from 21 PCT patients, 16 of whom were infected with hepatitis C virus (HCV), and from a separate group of 9 patients with HCV infection but not PCT. Thirteen PCT patients were studied when they had active disease and 8 after treatment-induced remission. Plasma ascorbic acid was low (
Peter D. Siersema - One of the best experts on this subject based on the ideXlab platform.
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Ferritin accumulation and Uroporphyrin crystal formation in hepatocytes of C57BL/10 mice: a time-course study
Cell and Tissue Research, 1993Co-Authors: Peter D. Siersema, Maud I. Cleton-soeteman, Wim C. Bruijn, Fiebo J. W. Kate, Henk G. Eijk, J. H. Paul WilsonAbstract:To establish the time-sequence relationship between ferritin accumulation and Uroporphyrin crystal formation in livers of C57BL/10 mice, a biochemical, morphological and morphometrical study was performed. Uroporphyria was induced by the intraperitoneal administration of hexachlorobenzene plus iron dextran and of iron dextran alone. Uroporphyrin crystal formation started in hepatocytes of mice treated with hexachlorobenzene plus iron dextran at 2 weeks and in mice treated with iron dextran alone at 9 weeks. In the course of time, Uroporphyrin crystals gradually increased in size. Uroporphyrin crystals were initially formed in hepatocytes in the periportal areas of the liver, in which also ferric iron staining was first detected. The amount and the distribution of the main storage form of iron in hepatocytes, ferritin, did not differ between the two treatment groups. Ferritin accumulation preceded the formation of Uroporphyrin crystals in hepatocytes in both treatment groups. Moreover, Uroporphyrin crystals were nearly always found close to ferritin iron. We conclude that Uroporphyrin crystals are only formed in hepatocytes in which also iron (ferritin) accumulates. Hexachlorobenzene accelerates the effects of iron in porphyrin metabolism, but does not influence the accumulation of iron into the liver.
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ferritin accumulation and Uroporphyrin crystal formation in hepatocytes of c57bl 10 mice a time course study
Cell and Tissue Research, 1993Co-Authors: Peter D. Siersema, Wim C. Bruijn, Maud I Cletonsoeteman, Fiebo Ten J W Kate, Henk G Van Eijk, J Paul H WilsonAbstract:To establish the time-sequence relationship between ferritin accumulation and Uroporphyrin crystal formation in livers of C57BL/10 mice, a biochemical, morphological and morphometrical study was performed. Uroporphyria was induced by the intraperitoneal administration of hexachlorobenzene plus iron dextran and of iron dextran alone. Uroporphyrin crystal formation started in hepatocytes of mice treated with hexachlorobenzene plus iron dextran at 2 weeks and in mice treated with iron dextran alone at 9 weeks. In the course of time, Uroporphyrin crystals gradually increased in size. Uroporphyrin crystals were initially formed in hepatocytes in the periportal areas of the liver, in which also ferric iron staining was first detected. The amount and the distribution of the main storage form of iron in hepatocytes, ferritin, did not differ between the two treatment groups. Ferritin accumulation preceded the formation of Uroporphyrin crystals in hepatocytes in both treatment groups. Moreover, Uroporphyrin crystals were nearly always found close to ferritin iron. We conclude that Uroporphyrin crystals are only formed in hepatocytes in which also iron (ferritin) accumulates. Hexachlorobenzene accelerates the effects of iron in porphyrin metabolism, but does not influence the accumulation of iron into the liver.
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Iron and Uroporphyrin in hepatocytes of inbred mice in experimental porphyria : a biochemical and morphological study
Hepatology (Baltimore Md.), 1991Co-Authors: Peter D. Siersema, Wim C. Bruijn, J. H. Paul Wilson, René P. Van Helvoirt, Diane A. M. Ketelaars, Maud I. Cleton, Henk G Van EijkAbstract:Hexachlorobenzene-induced porphyria is iron dependent and characterized by the decreased activity of Uroporphyrinogen decarboxylase and the accumulation of porphyrins in the liver. To examine the relationship between iron and porphyrins in liver tissue, we performed a biochemical and morphological (histological, ultrastructural and morphometrical) study in the livers of C57BL/10 mice. Mice were treated with hexachlorobenzene, iron dextran or the combination of hexachlorobenzene and iron dextran. An accumulation of porphyrins and an increased total iron content were found not only in the livers of mice treated with hexachlorobenzene and iron dextran but also in mice treated with iron dextran alone. In contrast, the amount of porphyrins was only slightly increased in the livers of mice treated with hexachlorobenzene alone. Needle-like structures, representing Uroporphyrin crystals, were observed, histologically and ultrastructurally, in hepatocytes of mice treated with hexachlorobenzene and iron dextran and with iron dextran alone. Uroporphyrin crystals and ferritin iron were found in the same hepatocyte. A single Uroporphyrin crystal, surrounded by ferritin iron, was observed in a hepatocyte of a mouse treated with hexachlorobenzene alone. Both in the livers of mice treated with hexachlorobenzene and iron dextran and in the livers of mice treated with iron dextran alone, morphometrical analysis showed that an increased area fraction of Uroporphyrin crystals was associated with an increased area fraction of ferritin iron in hepatocytes. Conclusions: In C57BL/10 mice, experimental porphyria can be induced by iron overload alone; Uroporphyrin crystals and ferritin iron are located in the same hepatocyte; and the morphological co-occurrence of Uroporphyrin crystals and ferritin iron in hepatocytes suggests a role for iron (as ferritin) in the pathogenesis of porphyria. (HEPATOLOGY 1991;14:1179–1188.)
J. H. Paul Wilson - One of the best experts on this subject based on the ideXlab platform.
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Ferritin accumulation and Uroporphyrin crystal formation in hepatocytes of C57BL/10 mice: a time-course study
Cell and Tissue Research, 1993Co-Authors: Peter D. Siersema, Maud I. Cleton-soeteman, Wim C. Bruijn, Fiebo J. W. Kate, Henk G. Eijk, J. H. Paul WilsonAbstract:To establish the time-sequence relationship between ferritin accumulation and Uroporphyrin crystal formation in livers of C57BL/10 mice, a biochemical, morphological and morphometrical study was performed. Uroporphyria was induced by the intraperitoneal administration of hexachlorobenzene plus iron dextran and of iron dextran alone. Uroporphyrin crystal formation started in hepatocytes of mice treated with hexachlorobenzene plus iron dextran at 2 weeks and in mice treated with iron dextran alone at 9 weeks. In the course of time, Uroporphyrin crystals gradually increased in size. Uroporphyrin crystals were initially formed in hepatocytes in the periportal areas of the liver, in which also ferric iron staining was first detected. The amount and the distribution of the main storage form of iron in hepatocytes, ferritin, did not differ between the two treatment groups. Ferritin accumulation preceded the formation of Uroporphyrin crystals in hepatocytes in both treatment groups. Moreover, Uroporphyrin crystals were nearly always found close to ferritin iron. We conclude that Uroporphyrin crystals are only formed in hepatocytes in which also iron (ferritin) accumulates. Hexachlorobenzene accelerates the effects of iron in porphyrin metabolism, but does not influence the accumulation of iron into the liver.
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Iron and Uroporphyrin in hepatocytes of inbred mice in experimental porphyria : a biochemical and morphological study
Hepatology (Baltimore Md.), 1991Co-Authors: Peter D. Siersema, Wim C. Bruijn, J. H. Paul Wilson, René P. Van Helvoirt, Diane A. M. Ketelaars, Maud I. Cleton, Henk G Van EijkAbstract:Hexachlorobenzene-induced porphyria is iron dependent and characterized by the decreased activity of Uroporphyrinogen decarboxylase and the accumulation of porphyrins in the liver. To examine the relationship between iron and porphyrins in liver tissue, we performed a biochemical and morphological (histological, ultrastructural and morphometrical) study in the livers of C57BL/10 mice. Mice were treated with hexachlorobenzene, iron dextran or the combination of hexachlorobenzene and iron dextran. An accumulation of porphyrins and an increased total iron content were found not only in the livers of mice treated with hexachlorobenzene and iron dextran but also in mice treated with iron dextran alone. In contrast, the amount of porphyrins was only slightly increased in the livers of mice treated with hexachlorobenzene alone. Needle-like structures, representing Uroporphyrin crystals, were observed, histologically and ultrastructurally, in hepatocytes of mice treated with hexachlorobenzene and iron dextran and with iron dextran alone. Uroporphyrin crystals and ferritin iron were found in the same hepatocyte. A single Uroporphyrin crystal, surrounded by ferritin iron, was observed in a hepatocyte of a mouse treated with hexachlorobenzene alone. Both in the livers of mice treated with hexachlorobenzene and iron dextran and in the livers of mice treated with iron dextran alone, morphometrical analysis showed that an increased area fraction of Uroporphyrin crystals was associated with an increased area fraction of ferritin iron in hepatocytes. Conclusions: In C57BL/10 mice, experimental porphyria can be induced by iron overload alone; Uroporphyrin crystals and ferritin iron are located in the same hepatocyte; and the morphological co-occurrence of Uroporphyrin crystals and ferritin iron in hepatocytes suggests a role for iron (as ferritin) in the pathogenesis of porphyria. (HEPATOLOGY 1991;14:1179–1188.)
J Paul H Wilson - One of the best experts on this subject based on the ideXlab platform.
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ferritin accumulation and Uroporphyrin crystal formation in hepatocytes of c57bl 10 mice a time course study
Cell and Tissue Research, 1993Co-Authors: Peter D. Siersema, Wim C. Bruijn, Maud I Cletonsoeteman, Fiebo Ten J W Kate, Henk G Van Eijk, J Paul H WilsonAbstract:To establish the time-sequence relationship between ferritin accumulation and Uroporphyrin crystal formation in livers of C57BL/10 mice, a biochemical, morphological and morphometrical study was performed. Uroporphyria was induced by the intraperitoneal administration of hexachlorobenzene plus iron dextran and of iron dextran alone. Uroporphyrin crystal formation started in hepatocytes of mice treated with hexachlorobenzene plus iron dextran at 2 weeks and in mice treated with iron dextran alone at 9 weeks. In the course of time, Uroporphyrin crystals gradually increased in size. Uroporphyrin crystals were initially formed in hepatocytes in the periportal areas of the liver, in which also ferric iron staining was first detected. The amount and the distribution of the main storage form of iron in hepatocytes, ferritin, did not differ between the two treatment groups. Ferritin accumulation preceded the formation of Uroporphyrin crystals in hepatocytes in both treatment groups. Moreover, Uroporphyrin crystals were nearly always found close to ferritin iron. We conclude that Uroporphyrin crystals are only formed in hepatocytes in which also iron (ferritin) accumulates. Hexachlorobenzene accelerates the effects of iron in porphyrin metabolism, but does not influence the accumulation of iron into the liver.
Wim C. Bruijn - One of the best experts on this subject based on the ideXlab platform.
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Ferritin accumulation and Uroporphyrin crystal formation in hepatocytes of C57BL/10 mice: a time-course study
Cell and Tissue Research, 1993Co-Authors: Peter D. Siersema, Maud I. Cleton-soeteman, Wim C. Bruijn, Fiebo J. W. Kate, Henk G. Eijk, J. H. Paul WilsonAbstract:To establish the time-sequence relationship between ferritin accumulation and Uroporphyrin crystal formation in livers of C57BL/10 mice, a biochemical, morphological and morphometrical study was performed. Uroporphyria was induced by the intraperitoneal administration of hexachlorobenzene plus iron dextran and of iron dextran alone. Uroporphyrin crystal formation started in hepatocytes of mice treated with hexachlorobenzene plus iron dextran at 2 weeks and in mice treated with iron dextran alone at 9 weeks. In the course of time, Uroporphyrin crystals gradually increased in size. Uroporphyrin crystals were initially formed in hepatocytes in the periportal areas of the liver, in which also ferric iron staining was first detected. The amount and the distribution of the main storage form of iron in hepatocytes, ferritin, did not differ between the two treatment groups. Ferritin accumulation preceded the formation of Uroporphyrin crystals in hepatocytes in both treatment groups. Moreover, Uroporphyrin crystals were nearly always found close to ferritin iron. We conclude that Uroporphyrin crystals are only formed in hepatocytes in which also iron (ferritin) accumulates. Hexachlorobenzene accelerates the effects of iron in porphyrin metabolism, but does not influence the accumulation of iron into the liver.
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ferritin accumulation and Uroporphyrin crystal formation in hepatocytes of c57bl 10 mice a time course study
Cell and Tissue Research, 1993Co-Authors: Peter D. Siersema, Wim C. Bruijn, Maud I Cletonsoeteman, Fiebo Ten J W Kate, Henk G Van Eijk, J Paul H WilsonAbstract:To establish the time-sequence relationship between ferritin accumulation and Uroporphyrin crystal formation in livers of C57BL/10 mice, a biochemical, morphological and morphometrical study was performed. Uroporphyria was induced by the intraperitoneal administration of hexachlorobenzene plus iron dextran and of iron dextran alone. Uroporphyrin crystal formation started in hepatocytes of mice treated with hexachlorobenzene plus iron dextran at 2 weeks and in mice treated with iron dextran alone at 9 weeks. In the course of time, Uroporphyrin crystals gradually increased in size. Uroporphyrin crystals were initially formed in hepatocytes in the periportal areas of the liver, in which also ferric iron staining was first detected. The amount and the distribution of the main storage form of iron in hepatocytes, ferritin, did not differ between the two treatment groups. Ferritin accumulation preceded the formation of Uroporphyrin crystals in hepatocytes in both treatment groups. Moreover, Uroporphyrin crystals were nearly always found close to ferritin iron. We conclude that Uroporphyrin crystals are only formed in hepatocytes in which also iron (ferritin) accumulates. Hexachlorobenzene accelerates the effects of iron in porphyrin metabolism, but does not influence the accumulation of iron into the liver.
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Iron and Uroporphyrin in hepatocytes of inbred mice in experimental porphyria : a biochemical and morphological study
Hepatology (Baltimore Md.), 1991Co-Authors: Peter D. Siersema, Wim C. Bruijn, J. H. Paul Wilson, René P. Van Helvoirt, Diane A. M. Ketelaars, Maud I. Cleton, Henk G Van EijkAbstract:Hexachlorobenzene-induced porphyria is iron dependent and characterized by the decreased activity of Uroporphyrinogen decarboxylase and the accumulation of porphyrins in the liver. To examine the relationship between iron and porphyrins in liver tissue, we performed a biochemical and morphological (histological, ultrastructural and morphometrical) study in the livers of C57BL/10 mice. Mice were treated with hexachlorobenzene, iron dextran or the combination of hexachlorobenzene and iron dextran. An accumulation of porphyrins and an increased total iron content were found not only in the livers of mice treated with hexachlorobenzene and iron dextran but also in mice treated with iron dextran alone. In contrast, the amount of porphyrins was only slightly increased in the livers of mice treated with hexachlorobenzene alone. Needle-like structures, representing Uroporphyrin crystals, were observed, histologically and ultrastructurally, in hepatocytes of mice treated with hexachlorobenzene and iron dextran and with iron dextran alone. Uroporphyrin crystals and ferritin iron were found in the same hepatocyte. A single Uroporphyrin crystal, surrounded by ferritin iron, was observed in a hepatocyte of a mouse treated with hexachlorobenzene alone. Both in the livers of mice treated with hexachlorobenzene and iron dextran and in the livers of mice treated with iron dextran alone, morphometrical analysis showed that an increased area fraction of Uroporphyrin crystals was associated with an increased area fraction of ferritin iron in hepatocytes. Conclusions: In C57BL/10 mice, experimental porphyria can be induced by iron overload alone; Uroporphyrin crystals and ferritin iron are located in the same hepatocyte; and the morphological co-occurrence of Uroporphyrin crystals and ferritin iron in hepatocytes suggests a role for iron (as ferritin) in the pathogenesis of porphyria. (HEPATOLOGY 1991;14:1179–1188.)
