Prevention of murine erythropoietic protoporphyria-associated skin photosensitivity and liver disease by dermal and hepatic ferrochelatase.
Erythropoietic protoporphyria (EPP) is caused by a defect in ferrochelatase, leading to the accumulation of protoporphyrin predominantly in erythrocytes and hepatocytes, and resulting in skin photosensitivity upon leaching of blood protoporphyrin into the skin. Some patients also develop severe liver damage. Because the respective contributions of hepatic and erythrocytic protoporphyrin to the pathophysiology of EPP remain unclear, we investigated this question using the murine model of EPP. Transplantation of bone marrow from EPP mice to normal recipients resulted in elevated erythrocyte and plasma protoporphyrin levels. However, quantification of serum liver enzymes and bilirubin together with histopathologic examination of liver sections of mice up to 16 months post-transplantation showed no evidence of liver damage. Moreover, despite massive elevation of serum protoporphyrin, transplanted mice showed minimal evidence of skin photosensitivity. Photosensitivity could also be prevented locally by implanting skin grafts from normal mice onto the backs of EPP recipients. These data validate the hypothesis that the main source of toxic protoporphyrin originates from the erythrocytes. However, we unexpectedly observed that normal ferrochelatase activity in hepatic and dermal cells of wild-type mice is sufficient to prevent liver disease and significant skin photosensitivity. These findings may provide new strategies for the treatment of EPP.
Pawliuk
Robert
R
Massachusetts Institute of Technology, Division of Health Sciences & Technology, Cambridge, Massachusetts 02115, USA.
Tighe
Robert
R
Wise
Robert J
RJ
Mathews-Roth
Micheline M
MM
Leboulch
Philippe
P
D000818:Animals; D016026:Bone Marrow Transplantation; D020405:Dermis / Q000201:enzymology; D004912:Erythrocytes / Q000378:metabolism; D005260:Female; D005294:Ferrochelatase / Q000235:genetics / Q000378:metabolism*; D008099:Liver / Q000201:enzymology; D008107:Liver Diseases / Q000209:etiology / Q000378:metabolism / Q000517:prevention & control*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008817:Mice, Mutant Strains; D010787:Photosensitivity Disorders / Q000209:etiology / Q000378:metabolism / Q000517:prevention & control*; D046351:Protoporphyria, Erythropoietic / Q000150:complications* / Q000378:metabolism; D011524:Protoporphyrins / Q000097:blood; D016038:Skin Transplantation
D011524:Protoporphyrins; D005294:Ferrochelatase