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1.
Photodermatol Photoimmunol Photomed ; 36(1): 29-33, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31374130

RESUMO

BACKGROUND: Erythropoietic protoporphyria (EPP) is a semi-dominantly inherited porphyria presenting with photosensitivity during early childhood. Acquired EPP has been reported; however, data regarding this rare disorder are scarce. PURPOSE: To evaluate the characteristics of acquired EPP. METHODS: A comprehensive search of PubMed, Google Scholar, ScienceDirect, and clinicaltrials.gov databases was performed by three reviewers. Studies describing patients with acquired EPP were included. Additionally, we present an index case of a 26-year-old patient who acquired clinically and biochemically typical EPP in association with myelodysplastic syndrome (MDS). RESULTS: We included 20 case reports describing 20 patients. Most (80%) patients were male of mean age 58 ± 13 years. In all patients, acquired EPP was associated with hematological disease, most commonly MDS (85%) followed by myeloproliferative disease (10%). In 86% of cases, hematological disease led to abnormality or somatic mutation in chromosome 18q (the locus of the ferrochelatase gene). The mean erythrocyte protoporphyrin IX concentration was very high (4286 µg/dL). Most (90%) patients presented with photosensitivity, 20% experienced blistering, and 25% presented with hepatic insufficiency, both uncommon in EPP. In 55% of patients, hematological disease was diagnosed after occurrence of cutaneous symptoms. Beta-carotene led to partial control of symptoms in 5 patients and resolution in another patient. Azacitidine treatment of MDS led to resolution of cutaneous symptoms in three patients. CONCLUSION: We present the distinct features of acquired EPP and highlight that any patient presenting with new-onset photosensitivity, irrespective of age should be evaluated for porphyria.


Assuntos
Azacitidina/uso terapêutico , Síndromes Mielodisplásicas , Transtornos de Fotossensibilidade , Protoporfiria Eritropoética , beta Caroteno/uso terapêutico , Adulto , Idoso , Cromossomos Humanos Par 18/genética , Cromossomos Humanos Par 18/metabolismo , Eritrócitos/metabolismo , Feminino , Ferroquelatase/genética , Ferroquelatase/metabolismo , Loci Gênicos , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Síndromes Mielodisplásicas/tratamento farmacológico , Síndromes Mielodisplásicas/genética , Síndromes Mielodisplásicas/metabolismo , Transtornos de Fotossensibilidade/induzido quimicamente , Transtornos de Fotossensibilidade/tratamento farmacológico , Transtornos de Fotossensibilidade/genética , Transtornos de Fotossensibilidade/metabolismo , Protoporfiria Eritropoética/induzido quimicamente , Protoporfiria Eritropoética/tratamento farmacológico , Protoporfiria Eritropoética/genética , Protoporfiria Eritropoética/metabolismo , Protoporfirinas/genética , Protoporfirinas/metabolismo
2.
Biomed Res Int ; 2015: 436319, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25945334

RESUMO

The effect of bile acids administration to an experimental mice model of Protoporphyria produced by griseofulvin (Gris) was investigated. The aim was to assess whether porphyrin excretion could be accelerated by bile acids treatment in an attempt to diminish liver damage induced by Gris. Liver damage markers, heme metabolism, and oxidative stress parameters were analyzed in mice treated with Gris and deoxycholic (DXA), dehydrocholic (DHA), chenodeoxycholic, or ursodeoxycholic (URSO). The administration of Gris alone increased the activities of glutathione reductase (GRed), superoxide dismutase (SOD), alkaline phosphatase (AP), gamma glutamyl transpeptidase (GGT), and glutathione-S-transferase (GST), as well as total porphyrins, glutathione (GSH), and cytochrome P450 (CYP) levels in liver. Among the bile acids studied, DXA and DHA increased PROTO IX excretion, DXA also abolished the action of Gris, reducing lipid peroxidation and hepatic GSH and CYP levels, and the activities of GGT, AP, SOD, and GST returned to control values. However, porphyrin accumulation was not prevented by URSO; instead this bile acid reduced ALA-S and the antioxidant defense enzymes system activities. In conclusion, we postulate that DXA acid would be more effective to prevent liver damage induced by Gris.


Assuntos
Doença Hepática Induzida por Substâncias e Drogas/tratamento farmacológico , Estresse Oxidativo/efeitos dos fármacos , Protoporfiria Eritropoética/tratamento farmacológico , Animais , Catalase/metabolismo , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Doença Hepática Induzida por Substâncias e Drogas/patologia , Ácido Quenodesoxicólico/administração & dosagem , Ácido Desidrocólico/administração & dosagem , Ácido Desoxicólico/administração & dosagem , Glutationa Peroxidase/metabolismo , Glutationa Redutase/metabolismo , Glutationa Transferase/metabolismo , Griseofulvina/toxicidade , Humanos , Peroxidação de Lipídeos/efeitos dos fármacos , Camundongos , Porfirinas/metabolismo , Protoporfiria Eritropoética/induzido quimicamente , Protoporfiria Eritropoética/metabolismo , Superóxido Dismutase/metabolismo , Ácido Ursodesoxicólico/administração & dosagem
3.
Cell Mol Biol (Noisy-le-grand) ; 55(2): 127-39, 2009 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-19656461

RESUMO

Erythropoietic Protoporphyria (EPP) is a disease associated with ferrochelatase deficiency, which produces accumulation of protoporphyrin IX (PROTO IX) in erythrocytes, liver and skin. In some cases, a severe hepatic failure and cholestasis was observed. Griseofulvin (Gris) develops an experimental EPP with hepatic manifestations in animals. The aim of this work was to further characterize this model studying its effect on different metabolisms in mice Gris feeding (0-2.5%, 7 and 14 days). PROTO IX accumulation in liver, blood and feces, induction of ALA-S activity, and a low rate of Holo/Apo tryptophan pyrrolase activity was produced, indicating a reduction of free heme pool. The progressive liver injury was reflected by the aspect and the enlargement of liver and the induction of hepatic damage. Liver redox balance was altered due to porphyrin high concentrations; as a consequence, the antioxidant defense system was disrupted. Heme oxygenase was also induced, however, at higher concentrations of antifungal, the free heme pool would be so depleted that this enzyme would not be necessary. In conclusion, our model of Protoporphyria produced liver alterations similar to those found in EPP patients.


Assuntos
Antifúngicos/toxicidade , Griseofulvina/toxicidade , Fígado/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Animais , Hidrocarboneto de Aril Hidroxilases/metabolismo , Citocromo P-450 CYP2A6 , Citocromo P-450 CYP3A/metabolismo , Modelos Animais de Doenças , Heme/metabolismo , Heme Oxigenase (Desciclizante)/metabolismo , Imuno-Histoquímica , Fígado/patologia , Masculino , Camundongos , Protoporfiria Eritropoética/induzido quimicamente , Protoporfirinas/metabolismo , Triptofano Oxigenase/metabolismo
5.
Physiol Res ; 55 Suppl 2: S93-101, 2006.
Artigo em Inglês | MEDLINE | ID: mdl-17298226

RESUMO

Erythropoietic protoporphyria (EPP) is an inherited disorder of heme biosynthesis caused by partial ferrochelatase deficiency, resulting in protoporphyrin overproduction which is responsible for painful skin photosensitivity. Chronic liver disease is the most severe complication of EPP, requiring liver transplantation in some patients. Data from a mouse model suggest that cytotoxic bile formation with high concentrations of bile salts and protoporphyrin may cause biliary fibrosis by damaging bile duct epithelium. In humans, cholestasis is a result of intracellular and canalicular precipitation of protoporphyrin. To limit liver damage two strategies may be considered: the first is to reduce protoporphyrin production and the second is to enhance protoporphyrin excretion. Bile salts are known to increase protoporphyrin excretion via the bile, while heme arginate is used to decrease the production of porphyrins in acute attacks of hepatic porphyrias. The Griseofulvin-induced protoporphyria mouse model has been used to study several aspects of human protoporphyria including the effects of bile salts. However, the best EPP animal model is an ethylnitrosourea-induced point mutation with fully recessive transmission, named ferrochelatase deficiency (Fech(m1Pas)). Here we investigate the effect of early ursodesoxycholic acid (UDCA) administration and heme-arginate injections on the ferrochelatase deficient EPP mouse model. In this model UDCA administration and heme-arginate injections do not improve the protoporphyric condition of Fech(m1Pas)/Fech(m1Pas) mice.


Assuntos
Arginina/uso terapêutico , Colagogos e Coleréticos/uso terapêutico , Heme/uso terapêutico , Protoporfiria Eritropoética/tratamento farmacológico , Ácido Ursodesoxicólico/uso terapêutico , Animais , Arginina/administração & dosagem , Colagogos e Coleréticos/administração & dosagem , Modelos Animais de Doenças , Hematopoese/efeitos dos fármacos , Heme/administração & dosagem , Injeções Intraperitoneais , Fígado/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Camundongos , Camundongos Transgênicos , Protoporfiria Eritropoética/induzido quimicamente , Ácido Ursodesoxicólico/administração & dosagem
6.
Am J Pathol ; 166(4): 1041-53, 2005 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-15793285

RESUMO

BALB/c Fech(m1Pas) mice have a mutated ferrochelatase gene resulting in protoporphyria that models the hepatic injury occurring sporadically in human erythropoietic protoporphyria. We used this mouse model to study the development of the injury and to compare the dysfunction of heme synthesis with hepatic gene expression of liver metabolism, oxidative stress, and cellular injury/inflammation. From an early age expression of total cytochrome P450 and many of its isoforms was significantly lower than in wild-type mice. However, despite massive accumulation of protoporphyrin in the liver, expression of the main genes controlling heme synthesis and catabolism (Alas1 and Hmox1, respectively) were only modestly affected even in the presence of the cytochrome P450-inducing CAR agonist 1,4-bis[2-(3,5-dichloropyridyloxy)]benzene. In contrast, in BALB/c mice exhibiting griseofulvin-induced hepatic protoporphyria with induction and destruction of cytochrome P450, both Alas1 and Hmox1 genes were markedly up-regulated. Other expression profiles in BALB/c Fech(m1Pas) mice identified roles for oxidative mechanisms in liver injury while modulated gene expression of hepatocyte transport proteins and cholesterol and bile acid synthesis illustrated the development of cholestasis. Subsequent inflammation and cirrhosis were also shown by the up-regulation of cytokine, cell cycling, and procollagen genes. Thus, gene expression profiles studied in Fech(m1Pas) mice may provide candidates for human polymorphisms that explain the sporadic hepatic consequences of erythropoietic protoporphyria.


Assuntos
Envelhecimento , Heme/metabolismo , Fígado/patologia , Protoporfiria Eritropoética/genética , Animais , Antifúngicos/toxicidade , Colestase/induzido quimicamente , Colestase/genética , Colestase/patologia , Modelos Animais de Doenças , Expressão Gênica , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Griseofulvina/toxicidade , Heme/genética , Hemeproteínas/genética , Hemeproteínas/metabolismo , Immunoblotting , Fígado/fisiologia , Masculino , Camundongos , Protoporfiria Eritropoética/induzido quimicamente , Protoporfiria Eritropoética/patologia , Protoporfirinas/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa
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