A mouse model of familial porphyria cutanea tarda

Phillips, John D.

doi:10.1073/pnas.011481398

Cited by 27 publications

(27 citation statements)

References 18 publications

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“…But in a cardiac ischemia-reperfusion experiment, injury is exaggerated in Hfe À/À mice on a high iron diet (Turoczi et al, 2003). Similarly, Hfe À/À mice with hepatic iron overload do not accumulate porphyrins in their livers, unless they also have an inactivating mutation in one allele of the uroporphyrinogen decarboxylase gene (Phillips et al, 2001).…”

Section: Figurementioning

confidence: 97%

Iron in Skin of Mice with Three Etiologies of Systemic Iron Overload

Adams

Lazova

Andrews

et al. 2005

Journal of Investigative Dermatology

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In human hemochromatosis, tissue toxicity is a function of tissue iron levels. Despite reports of skin toxicity in hemochromatosis, little is known about iron levels in skin of individuals with systemic iron overload. We measured skin iron and studied skin histology in three mouse models of systemic iron overload: mice with a deletion of the hemochromatosis (Hfe) gene, mice fed a high iron diet, and mice given parenteral injections of iron. In Hfe(-/-) mice, iron content in the epidermis and dermis was unexpectedly the same as in Hfe(+/+) mice, and there were no histological abnormalities detected after 30 wk. A high iron diet produced increased iron in the epidermis of both normal and Hfe(-/-) animals; a high diet increased iron in the dermis only in Hfe(-/-) mice. Increased skin iron was not associated with other histological changes, even after 19 wk. Parenteral administration of iron produced increased iron in the epidermis and dermis, and gave the skin a bronze hue. These results show that the amount and distribution of iron in the skin depends on the etiology of iron overload. It appears that neither Hfe deletion nor elevated skin iron alone can account for cutaneous manifestations reportedly seen in humans with hereditary hemochromatosis.

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Section: Figurementioning

confidence: 97%

Iron in Skin of Mice with Three Etiologies of Systemic Iron Overload

Adams

Lazova

Andrews

et al. 2005

Journal of Investigative Dermatology

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“…More recently, some oxidized aliphatic chain and mesohydroxyuroporphyrins have been detected in excreta (10). The porphyrins occurring in mouse uroporphyrias are much less characterized, and only preliminary identification by HPLC has been reported (19,20,28), although these models of PCT are those now most commonly investigated in a variety of mechanistic studies (1,3,5,29). In this work, using HPLC/MS, we demonstrated the presence of uroporphyrin I and III isomers induced in the liver of mice following the administration of TCDD and enhanced by iron.…”

Section: Discusssionmentioning

confidence: 97%

“…Coproporphyrinogen III is further metabolized to form the heme, whereas coproporphyrinogen I has no biological function and is excreted (Scheme 1) (4). Depressing the activity of UROD below a threshold is associated with massive accumulation and excretion of uroporphyrinogens and partially decarboxylated analogues (1)(2)(3)5). Porphyrinogens are unstable and will readily oxidize by 6-electron withdrawal to the corresponding porphyrins that account for the characteristic fluorescence of tissue and excreta in porphyria.…”

Section: Introductionmentioning

confidence: 99%

Dihydroxy-, Hydroxyspirolactone-, and Dihydroxyspirolactone-urochlorins Induced by 2,3,7,8-Tetrachlorodibenzo-p-dioxin in the Liver of Mice

Lim

Danton

Clothier

et al. 2006

Chem. Res. Toxicol.

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Previous work has shown that 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) causes porphyria, enhanced by iron, in C57BL/6J mice with marked accumulation in the liver of uroporphyrin I and III isomers and heptacarboxylic acid III and is one model of human porphyria cutanea tarda. Preliminary examination by HPLC also indicated the presence of some oxygenated side chain uroporphyrin derivatives. Here, the porphyrin constituents of TCDD-induced porphyric liver have been examined by HPLC/electrospray ionization quadrupole time-of-flight mass spectrometry (HPLC/ESI-Q-TOFMS) to characterize the major and minor porphyrins present in hepatic tissue. As well as the major constituents uroporphyrins I and III, we identified the isomers of heptacarboxylic, hexacarboxylic, and pentacarboxylic acid porphyrins arising from intermediates in the stepwise decarboxylation of uroporphyrinogen I and III to coproporphyrinogens. In addition, monohydroxy analogues of uroporphyrin isomers were detected hydroxylated in the acetic acid and beta-positions of propionic acid side chains and in the meso ring position. Of particular note, for the first time for human and experimental porphyrias, we found chlorins (dihydroxy-, hydroxyspirolactone- ,and dihydroxyspirolactone-urochlorins) consistent with those derived from an epoxyurochlorin structure, formed by oxidation of the double bond of a pyrrole ring of uroporphyrinogen I and III isomers. The findings demonstrate that oxygen insertion into the pyrrole rings of uroporphyrinogens occurs under pathological circumstances in vivo and support the evidence for an oxidative cellular environment present in TCDD-treated porphyric tissue.

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“…So wurde schon vor Kenntnis, dass das die Hämochromatose auslösende HEF Gen wie HLAGene auf Chromosom 6 ist, sowohl für diese Erkrankung als auch für die PCT eine HLAAssoziation mit HLAA3 und B7 aufgezeigt, was den engen Bezug der PCT zum Eisenstoff wechsel unterstreicht [8]. Die Kreuzung schließlich von Mäusen mit UROD Gendefekt und solchen mit homozygotem HFEDefekt führte zu Mäusen mit einer PCTSymptomatik [15]. Aber auch bei PCTPatienten ohne Mutationen in HFE findet sich erhöhte Eisenspeicherung bei verminderter Bildung von Hepcidin [20].…”

Section: Porphyria Cutanea Tarda Und Eisenstoffwechselunclassified

Porphyria cutanea tarda

Merk

2016

Hautarzt

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Porphyria cutanea tara (PCT) has a prevelance of about 40 new diagnoses per 1 million people per year and is the most frequently occurring type of porphyria worldwide. Inhibition of the uroporphyrinogen decarboxylase (UROD) is the main cause of the disease, which can be the result of a heterozygous or homozygous mutation of the UROD gene; however, xenobiotics or other diseases may play an important role for the precipitation of the disease. Risk factors include alcohol, estrogen, iron overload, and hemochromatosis, hepatitis C or poisoning, e.g., with polyhalogenated aromatic compounds such as hexachlorobenzene. Signs and symptoms are blisters, skin fragility, erosions hyperpigmentation, sclerodermoid plaques. Therapy includes sun protection, prevention of risk factors, phlebotomy, and chloroquine.

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A mouse model of familial porphyria cutanea tarda

Cited by 27 publications

References 18 publications

Iron in Skin of Mice with Three Etiologies of Systemic Iron Overload

Iron in Skin of Mice with Three Etiologies of Systemic Iron Overload

Dihydroxy-, Hydroxyspirolactone-, and Dihydroxyspirolactone-urochlorins Induced by 2,3,7,8-Tetrachlorodibenzo-p-dioxin in the Liver of Mice

Porphyria cutanea tarda

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