title: Mdr P-glycoproteins are not essential for biliary excretion of the hydrophobic heme precursor protoporphyrin in a griseofulvin-induced mouse model of erythropoietic protoporphyria.
abstract: 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 griseofulvin-treated 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.
authors.affiliation: Center for Liver, Digestive, and Metabolic Diseases, Groningen University Institute for Drug Exploration, Departments of Pediatrics and Gastroenterology, University Hospital Groningen, Groningen, The Netherlands.
authors.forename: Torsten
authors.initials: T
authors.lastname: Plösch
authors.forename: Vincent W
authors.initials: VW
authors.lastname: Bloks
authors.forename: Juul F W
authors.initials: JF
authors.lastname: Baller
authors.forename: Rick
authors.initials: R
authors.lastname: Havinga
authors.forename: Henkjan J
authors.initials: HJ
authors.lastname: Verkade
authors.forename: Peter L M
authors.initials: PL
authors.lastname: Jansen
authors.forename: Folkert
authors.initials: F
authors.lastname: Kuipers
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001646:Bile / Q000378:metabolism*; D006118:Griseofulvin / Q000494:pharmacology; D050356:Lipid Metabolism; D008055:Lipids / Q000097:blood; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D008297:Male; D051379:Mice; D018345:Mice, Knockout / Q000235:genetics; D017121:Porphyria, Hepatoerythropoietic / Q000139:chemically induced* / Q000378:metabolism*; D011524:Protoporphyrins / Q000378:metabolism*; D012016:Reference Values; D000097202:ATP-Binding Cassette Sub-Family B Member 4
chemical_list: D018435:ATP Binding Cassette Transporter, Subfamily B; D018528:ATP-Binding Cassette Transporters; D006118:Griseofulvin; D008055:Lipids; D011524:Protoporphyrins; D000097202:ATP-Binding Cassette Sub-Family B Member 4; C095122:multidrug resistance protein 3