title: Exogenous protoporphyrin inhibits Hep G2 cell proliferation, increases the intracellular hydrogen peroxide concentration and causes ultrastructural alterations.
abstract: Ultrastructural hepatocellular abnormalities in early stages of erythropoietic protoporphyria lead to hepatobiliary changes that cause overt liver disease in 5-10% of patients, not infrequently progressing to fulminant hepatic failure. This cannot be attributed solely to protoporphyrin crystal deposition in the liver. Hepatic redox systems have therefore been postulated as an equivalent for the photoreaction of protoporphyrin. We studied the dark effects of protoporphyrin and hematoporphyrin on HL60 and Hep G2 cells. Cell proliferation and intracellular H2O2 concentrations were assessed and related to the ultrastructural morphology. The incubation with protoporphyrin and hematoporphyrin resulted in a dose- and time-dependent inhibition of proliferation indices of Hep G2 cells. Flow cytometric analyses of intracellular H2O2 concentrations demonstrated a dose-dependent increase in both cell lines upon incubation with protoporphyrin. Hep G2 cells displayed ultrastructural alteration of the endoplasmatic reticulum and plasma membranes. Also 'cell blebbing' occurred. We conclude that exogenous protoporphyrin increases the intracellular H2O2 concentration and exerts a cytotoxic dark effect. This may contribute to the liver injury observed in erythropoietic protoporphyria.
authors.affiliation: Department of Hepato-Gastroenterology, Utrecht State University Hospital, The Netherlands.
authors.forename: J C
authors.initials: JC
authors.lastname: Koningsberger
authors.forename: L H
authors.initials: LH
authors.lastname: Rademakers
authors.forename: J
authors.initials: J
authors.lastname: van Hattum
authors.forename: H B
authors.initials: HB
authors.lastname: de la Faille
authors.forename: L J
authors.initials: LJ
authors.lastname: Wiegman
authors.forename: E
authors.initials: E
authors.lastname: Italiaander
authors.forename: G P
authors.initials: GP
authors.lastname: van Berge Henegouwen
authors.forename: J J
authors.initials: JJ
authors.lastname: Marx
mesh_terms: D006528:Carcinoma, Hepatocellular / Q000473:pathology*; D002455:Cell Division / Q000187:drug effects; D006415:Hematoporphyrins / Q000494:pharmacology; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism*; D007425:Intracellular Membranes / Q000378:metabolism*; D008113:Liver Neoplasms / Q000473:pathology*; D008854:Microscopy, Electron; D009994:Osmolar Concentration; D011524:Protoporphyrins / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
chemical_list: D006415:Hematoporphyrins; D011524:Protoporphyrins; D006861:Hydrogen Peroxide