title: Breast cancer resistance protein (Bcrp1/Abcg2) is expressed in the harderian gland and mediates transport of conjugated protoporphyrin IX.
abstract: Proper regulation of intracellular levels of protoporphyrin IX (PPIX), the direct precursor of heme, is important for cell survival. A deficiency in ferrochelatase, which mediates the final step in heme biosynthesis, leads to erythropoietic protoporphyria (EPP), a photosensitivity syndrome caused by the accumulation of PPIX in the skin. We have previously shown that mice with a deficiency in the ABC transporter Bcrp1/Abcg2 display a novel type of protoporphyria. This protoporphyria is mild compared with ferrochelatase-dependent EPP, and in itself not sufficient to cause phototoxicity, but it might exacerbate the consequences of other porphyrias. In this study, we identified the mouse harderian gland as a novel expression site of Bcrp1. Because of its pronounced role in porphyrin secretion, the harderian gland presents a useful tool to study the mechanism of Bcrp1-related protoporphyria and transport of porphyrins. Bcrp1(-/-) harderian gland displayed a highly increased accumulation of PPIX glycoconjugates, and a similar shift was seen in Bcrp1(-/-) liver. Tear- and hepatobiliary excretion data suggest that Bcrp1 controls intracellular levels of PPIX by mediating high affinity transport of its glycoconjugates and possibly low-affinity transport of unconjugated PPIX. This mechanism may allow cells to prevent or reduce cytotoxicity of PPIX under excess conditions, without spillage under physiological conditions where PPIX is needed.
authors.affiliation: Div. of Experimental Therapy, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands.
authors.forename: Johan W
authors.initials: JW
authors.lastname: Jonker
authors.forename: Sandra
authors.initials: S
authors.lastname: Musters
authors.forename: Maria L H
authors.initials: ML
authors.lastname: Vlaming
authors.forename: Torsten
authors.initials: T
authors.lastname: Plösch
authors.forename: Karin E R
authors.initials: KE
authors.lastname: Gooijert
authors.forename: Michel J
authors.initials: MJ
authors.lastname: Hillebrand
authors.forename: Hilde
authors.initials: H
authors.lastname: Rosing
authors.forename: Jos H
authors.initials: JH
authors.lastname: Beijnen
authors.forename: Henkjan J
authors.initials: HJ
authors.lastname: Verkade
authors.forename: Alfred H
authors.initials: AH
authors.lastname: Schinkel
mesh_terms: D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001646:Bile / Q000378:metabolism; D001693:Biological Transport, Active / Q000502:physiology*; D005260:Female; D017353:Gene Deletion; D005786:Gene Expression Regulation; D006243:Harderian Gland / Q000033:anatomy & histology / Q000378:metabolism*; D008099:Liver / Q000378:metabolism; D008297:Male; D051379:Mice; D015394:Molecular Structure; D011524:Protoporphyrins / Q000737:chemistry / Q000378:metabolism*
chemical_list: D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; C501412:Abcg2 protein, mouse; D011524:Protoporphyrins; C028025:protoporphyrin IX