Uroporphyria caused by ethanol in Hfe (−/−) mice as a model for porphyria cutanea tarda

Sinclair, Peter R.; Gorman, Nadia; Trask, Heidi W.; Bement, William J.; Szakacs, Juliana G.; Elder, George H.; Balestra, Dominic J.; Sinclair, Jacqueline F.; Gerhard, Glenn S.

doi:10.1053/jhep.2003.50034

Cited by 18 publications

(10 citation statements)

References 50 publications

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“…Conventional models include exposure of cells to delta-aminolevulinate (ALA) for transient porphyria (42), chemical induction of hepatic porphyria (14), and random genetic mutations for producing porphyric mice (1,46), Saccharomyces cerevisiae (50), and zebra fish (49). Porphyria developed in these models is either of low level or not monospecific, thereby lacking sensitivity and specificity.…”

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confidence: 99%

TransgenicLeishmaniaModel for Delta-Aminolevulinate-Inducible Monospecific Uroporphyria: Cytolytic Phototoxicity Initiated by Singlet Oxygen-Mediated Inactivation of Proteins and Its Ablation by Endosomal Mobilization of Cytosolic Uroporphyrin

et al. 2008

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Inherent deficiencies of Leishmania in heme biosynthesis were genetically complemented for delta-aminolevulinate-inducible biosynthesis and accumulation of light-excitable uroporphyrin. The phototoxic flagellar immobilization and cytolysis phenotypes and porphyrin mobilization noted previously were further analyzed biochemically and cytologically to delineate the mechanism of phototoxicity and detoxification in this monoporphyric model. Under optimal conditions of induction for approximately 3 days, cells remained viable but became increasingly uroporphyric, peaking at >90% of the population by approximately day 2; thereafter, a small population of less porphyric or aporphyric cells emerged. On exposure to light, the flagella of porphyric cells were immobilized in milliseconds, and singlet oxygen became detectable in their lysates. Both photosensitive phenotypes increased proportionally with the cellular uroporphyric levels and were susceptible to inhibition by azide, but not by D-mannitol. Brief irradiation of the uroporphyric cells produced no appreciable protein degradation but inactivated cytosolic neomycin phosphotransferase and significantly bleached cytosolic green fluorescent protein, which was azide reversible. These cells were irreparably photodamaged, as indicated by their subsequent loss of membrane permeability and viability. This is the first in situ demonstration that early inactivation of functional proteins by singlet oxygen initiates the cytolytic phototoxicity in uroporphyria. Detoxification appears to involve endocytic/exocytic mobilization of uroporphyrin from cytosol to "porphyrinosomes" for its eventual extracellular expulsion. This is proposed as the sole mechanism of detoxification, since it is attributable to the reversion of porphyric to aporphyric cells during uroporphyrinogenesis and repeated cycles of this event plus photolysis selected no resistant mutants, only aporphyric clones of the parental phenotypes. Further characterization of the transport system for uroporphyrin in this model is expected to benefit not only our understanding of the cellular mechanism for disposal of toxic soluble wastes but also potentially the effective management of human uroporphyria and the use of uroporphyric Leishmania for vaccine/drug delivery.

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confidence: 99%

TransgenicLeishmaniaModel for Delta-Aminolevulinate-Inducible Monospecific Uroporphyria: Cytolytic Phototoxicity Initiated by Singlet Oxygen-Mediated Inactivation of Proteins and Its Ablation by Endosomal Mobilization of Cytosolic Uroporphyrin

et al. 2008

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“…l3 Histological grading was performed separately by two pathologists who agreed on the grading as described previously. 15 …”

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confidence: 99%

Genetic factors influence ethanol-induced uroporphyria in Hfe (—/—) mice

et al. 2004

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Two major risk factors for porphyria cutanea tarda (PCT) are alcohol consumption and homozygosity for the C282Y mutation in the hereditary hemochromatosis gene (HFE). We recently described an animal model for alcohol-induced uroporphyria, using Hfe(-/-) mice. In the present study we show that this effect is dependent on genetic background and ethanol dose. In the 129S6/SvEvTac (129) strain, treatment with 15% ethanol in the drinking water for 6.5 months produced an accumulation of hepatic uroporphyrin (URO) 4-fold higher than that observed with 10% ethanol, a 90% decrease in uroporphyrinogen decarboxylase activity (UROD), and further increased the activities of hepatic 5-aminolevulinate synthase (ALAS) and CYP1A2. Hepatic nonheme iron (NHFe) and hepatocyte iron staining were not further increased by 15% compared to 10% ethanol. Treatment of C57BL/6 Hfe(-/-) mice with 15% ethanol for 6.5 months did not increase hepatic URO. Although NHFe was increased by ethanol, the resulting level was only half that of ethanol-treated 129 Hfe(-/-) mice. ALAS induction was similar in both Hfe(-/-) strains. In wild-type 129 mice treated with ethanol for 6 to 7 months, administration of iron dextran increased hepatic URO accumulation and decreased UROD activity. In conclusion, this study demonstrates a strong effect of genetic background on ethanol-induced uroporphyria, which is probably due to a greater effect of ethanol on iron metabolism in the susceptible strain.

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“…There are certainly complex interactions between HFE, iron, alcohol and UROD in the liver, as shown in the mouse HFE–/– model [36, 37]. Alcohol induces decreased activity of hepatic UROD in this model, which is mainly mediated by hepatic iron metabolism [36]. Another study also suggested a strong effect of the genetic background [37].…”

Section: Discussionmentioning

confidence: 99%

“…This unexpected finding suggests that there might be an interaction between HFE mutations and erythrocytic UROD. There are certainly complex interactions between HFE, iron, alcohol and UROD in the liver, as shown in the mouse HFE–/– model [36, 37]. Alcohol induces decreased activity of hepatic UROD in this model, which is mainly mediated by hepatic iron metabolism [36].…”

Section: Discussionmentioning

confidence: 99%

Porphyria Cutanea Tarda, Hepatitis C, Uroporphyrinogen Decarboxylase and Mutations of HFE Gene

Cribier¹,

Chiavérini²,

Dali‐Youcef³

et al. 2008

Dermatology

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Background: Hemochromatosis gene (HFE) mutations and the hepatitis C virus (HCV) are known risk factors for porphyria cutanea tarda (PCT), but interactions with erythrocytic uroporphyrinogen decarboxylase (UROD) have seldom been addressed. Objective: In order toexamine the links between these factors, we conducted a multicentre prospective case-control study. Methods: PCT patients with (n = 32) or without HCV (n = 28) were matched to HCV+ (n = 32) and HCV– controls (n = 28). HFE mutations (C282Y and H63D) were analyzed by PCR. Results: PCT+/HCV+ patients were younger than PCT+/HCV– patients (46.9 vs. 58.2 years, p < 0.001). UROD values were not significantly different in HCV+ and HCV– patients. Both C282Y and H63D were more frequent in PCT+ patients than in controls, but there was no difference in HFE genotype according to HCV seropositivity. Mean UROD was lower in case of HFE mutations in both PCT patients and controls. Conclusion: In French patients, HCV infection is probably the major causal factor of PCT. It is not linked with HFE mutations, although they are significantly associated with PCT. A low erythrocytic UROD might be a predisposing factor. The UROD value was lower in patients with HFE mutations, suggesting a possible interaction between HFE genotype and UROD levels.

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Uroporphyria caused by ethanol in Hfe (−/−) mice as a model for porphyria cutanea tarda

Cited by 18 publications

References 50 publications

TransgenicLeishmaniaModel for Delta-Aminolevulinate-Inducible Monospecific Uroporphyria: Cytolytic Phototoxicity Initiated by Singlet Oxygen-Mediated Inactivation of Proteins and Its Ablation by Endosomal Mobilization of Cytosolic Uroporphyrin

TransgenicLeishmaniaModel for Delta-Aminolevulinate-Inducible Monospecific Uroporphyria: Cytolytic Phototoxicity Initiated by Singlet Oxygen-Mediated Inactivation of Proteins and Its Ablation by Endosomal Mobilization of Cytosolic Uroporphyrin

Genetic factors influence ethanol-induced uroporphyria in Hfe (—/—) mice

Porphyria Cutanea Tarda, Hepatitis C, Uroporphyrinogen Decarboxylase and Mutations of HFE Gene

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