The liver in protoporphyria

Bloomer, Joseph R.

doi:10.1002/hep.1840080235

Cited by 106 publications

(47 citation statements)

References 66 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…16,27 Griseofulvin induced typical biochemical signs of liver damage also present in human EPP patients 1,4,28 and in fech/fech mice. 29 Characteristically, PP concentrations both in erythrocytes and liver rose enormously in all 3 strains of mice on griseofulvin treatment.…”

Section: Discussionmentioning

confidence: 87%

“…5 PP is not enzymatically altered nor conjugated in the liver. 4 It is highly hydrophobic and is therefore removed from the body exclusively via the bile, followed by fecal excretion. 6 Mechanisms responsible for PP secretion into bile are currently not known.…”

Section: Hepatic Complications In Erythropoietic Protoporphyria (Epp)mentioning

confidence: 99%

“…3 In the liver, PP deposits can be found both in cells and in small bile channels. 4 Severe hepatic complications in EPP are relatively rare, but indicative for transplantation in up to 10% of all cases. 5 PP is not enzymatically altered nor conjugated in the liver.…”

mentioning

confidence: 99%

See 2 more Smart Citations

Mdr P-glycoproteins are not essential for biliary excretion of the hydrophobic heme precursor protoporphyrin in a griseofulvin-induced mouse model of erythropoietic protoporphyria

et al. 2002

View full text Add to dashboard Cite

Hepatic complications in erythropoietic protoporphyria (EPP) have been attributed to toxic actions of accumulated protoporphyrin (PP). PP can only be removed via the bile but transport systems involved have not been defined. The aim of this study was to gain insight in the mode of biliary PP excretion, with emphasis on the potential contribution of the Mdr1 P-glycoprotein export pump and biliary lipids as PP carriers. Control mice and mice homozygous for Mdr1a/b (Abcb1) or Mdr2 (Abcb4) gene disruption, the latter unable to secrete phospholipids and cholesterol into bile, were treated with griseofulvin to chemically induce protoporphyria. All groups showed dramatically increased PP levels in erythrocytes and liver after griseofulvin treatment. Histologically, massive PP deposits were found in livers of control and Mdr1a/b ؊/؊ mice but not in those of Mdr2 ؊/؊ mice. Serum unesterified cholesterol and phospholipids were increased by griseofulvin because of formation of lipoprotein-X in control and Mdr1a/b ؊/؊ mice only. Yet, bile flow was not impaired in griseofulvintreated mice, and biliary bile salt, phospholipid, and cholesterol secretion rates were significantly increased. Surprisingly, biliary PP excretion was similar in all 3 groups of griseofulvin-treated mice: the observed linear relationship between hepatic and biliary PP concentrations and identical liver-to-bile concentration ratios in treated and untreated mice suggest a passive mode of excretion. In conclusion, the data show that Mdr P-glycoproteins are not critically involved in biliary removal of excess PP and indicate that the presence of biliary lipids is required for formation of intrahepatic PP deposits. (HEPATOLOGY 2002;35: 299-306.) F errochelatase (EC 4.99.1.1) is a mitochondrial enzyme that transfers iron into protoporphyrin (PP) during the formation of heme. 1 In erythropoietic protoporphyria (EPP), an inherited disease caused by a mutated ferrochelatase gene, ferrochelatase activity is markedly reduced, i.e., in severe cases to 4% to 20% of control values. 2 Impaired ferrochelatase activity leads to a reduced heme synthesis rate and, via induction of the preceding steps in the biosynthetic cascade, to accumulation of the highly hydrophobic heme precursor PP in erythrocytes and liver. 1 Common clinical signs of EPP are erythema and edema caused by PP phototoxicity in the skin. 3 In the liver, PP deposits can be found both in cells and in small bile channels. 4 Severe hepatic complications in EPP are relatively rare, but indicative for transplantation in up to 10% of all cases. 5 PP is not enzymatically altered nor conjugated in the liver. 4 It is highly hydrophobic and is therefore removed from the body exclusively via the bile, followed by fecal excretion. 6 Mechanisms responsible for PP secretion into bile are currently not known. Previous studies performed by our laboratory showed association of PP with cholesterol/phospholipid vesicles in bile, 7 suggesting that these may act as PP carriers in this aqueous solution. Reduction of bilia...

show abstract

Section: Discussionmentioning

confidence: 87%

Section: Hepatic Complications In Erythropoietic Protoporphyria (Epp)mentioning

confidence: 99%

See 1 more Smart Citation

Mdr P-glycoproteins are not essential for biliary excretion of the hydrophobic heme precursor protoporphyrin in a griseofulvin-induced mouse model of erythropoietic protoporphyria

et al. 2002

View full text Add to dashboard Cite

show abstract

“…Malignant biliary obstruction in adults or biliary atresia in infants can lead to cirrhosis within one year (Scobie and Summerskill, 1965). Progression can be rapid also in protoporphyria (Bloomer, 1988). In contrast, hepatitis C typically requires more than 25 years to reach cirrhosis, in the absence of cofactors such as alcohol use (Poynard et al, 1997).…”

Section: Time-course and Reversibility Of Fibrosismentioning

confidence: 99%

Chronic liver injury, TGF-β, and cancer

Bissell

2001

Exp Mol Med

156

View full text Add to dashboard Cite

Cells termed myofibroblasts are prominent in the injury response of all epithelial tissues. They exhibit proliferation, migration, production of collagen and other extracellular matrix (ECM) molecules, and contraction, all for containing the injury and closing the wound. When the injury is limited in time, the final stage of the repair involves a dismantling of the cellular apparatus and restoration of normal tissue structure. With multiple cycles of repair, however, there is net accumulation of ECM, to the detriment of tissue structure and function. Repair-related ECM coalesces into fibrous bundles and, over time, undergoes changes that render it resistant to degradation. The result is a scar. In the skin, a scar may have cosmetic importance only. In the liver, however, extensive scarring is the setting for unregulated growth and neoplasia; also, fibrous bands disrupt normal blood flow, leading to portal hypertension and its complications. With regard to therapy for fibrosis, the first consideration is elimination of the injury factor. However, given that many liver diseases do not have effective therapies at present, strategies targeting fibrogenesis per se are under development. The main source of myofibroblast-like cells and ECM production in the liver is the perisinusoidal stellate cell, which responds to injury with a pleiotypic change termed activation. Activation is orchestrated by cytokines and the ECM itself. Among the cytokines involved in this process, transforming growth factor-beta (TGF-β) is particularly prominent. The early changes in ECM include de novo production of a specific "fetal" isoform of fibronectin, which arises from sinusoidal endothelial cells. It is stimulated by TGF-β and acts directly on stellate cells to promote their activation. Based on these and other advances in understanding the fundamentals of the injury response, several strategies now exist for altering fibrogenesis, ranging from agents that block TGF-β to traditional Chinese herbal extracts. Arrest of fibrogenesis, even with underlying cirrhosis, is likely to extend life or prolong the time to transplant. Whether it reduces the risk of hepatocellular carcinoma remains to be proven. Although TGF-β antagonists are effective anti-fibrogenic agents, they will require detailed safety testing because of the finding that several forms of epithelial neoplasia are associated with altered regulation of TGF-β.

show abstract

“…4.99.1.1). The enzyme is associated with the inner mitochondrial membrane and catalyzes the insertion of iron into protoporphyrin to form heme.…”

Section: Introductionmentioning

confidence: 97%

Successful therapeutic effect in a mouse model of erythropoietic protoporphyria by partial genetic correction and fluorescence-based selection of hematopoietic cells

Fontanellas

Méndez²,

Mazurier³

et al. 2001

Gene Ther

View full text Add to dashboard Cite

The liver in protoporphyria

Cited by 106 publications

References 66 publications

Mdr P-glycoproteins are not essential for biliary excretion of the hydrophobic heme precursor protoporphyrin in a griseofulvin-induced mouse model of erythropoietic protoporphyria

Mdr P-glycoproteins are not essential for biliary excretion of the hydrophobic heme precursor protoporphyrin in a griseofulvin-induced mouse model of erythropoietic protoporphyria

Chronic liver injury, TGF-β, and cancer

Successful therapeutic effect in a mouse model of erythropoietic protoporphyria by partial genetic correction and fluorescence-based selection of hematopoietic cells

Contact Info

Product

Resources

About