title: The breast cancer resistance protein protects against a major chlorophyll-derived dietary phototoxin and protoporphyria.
abstract: The breast cancer resistance protein (BCRPABCG2) is a member of the ATP-binding cassette family of drug transporters and confers resistance to various anticancer drugs. We show here that mice lacking Bcrp1Abcg2 become extremely sensitive to the dietary chlorophyll-breakdown product pheophorbide a, resulting in severe, sometimes lethal phototoxic lesions on light-exposed skin. Pheophorbide a occurs in various plant-derived foods and food supplements. Bcrp1 transports pheophorbide a and is highly efficient in limiting its uptake from ingested food. Bcrp1(-/-) mice also displayed a previously unknown type of protoporphyria. Erythrocyte levels of the heme precursor and phototoxin protoporphyrin IX, which is structurally related to pheophorbide a, were increased 10-fold. Transplantation with wild-type bone marrow cured the protoporphyria and reduced the phototoxin sensitivity of Bcrp1(-/-) mice. These results indicate that humans or animals with low or absent BCRP activity may be at increased risk for developing protoporphyria and diet-dependent phototoxicity and provide a striking illustration of the importance of drug transporters in protection from toxicity of normal food constituents.
authors.affiliation: Division of Experimental Therapy, The Netherlands Cancer Institute, 1066 CX Amsterdam, The Netherlands.
authors.forename: Johan W
authors.initials: JW
authors.lastname: Jonker
authors.forename: Marije
authors.initials: M
authors.lastname: Buitelaar
authors.forename: Els
authors.initials: E
authors.lastname: Wagenaar
authors.forename: Martin A
authors.initials: MA
authors.lastname: Van Der Valk
authors.forename: George L
authors.initials: GL
authors.lastname: Scheffer
authors.forename: Rik J
authors.initials: RJ
authors.lastname: Scheper
authors.forename: Torsten
authors.initials: T
authors.lastname: Plosch
authors.forename: Folkert
authors.initials: F
authors.lastname: Kuipers
authors.forename: Ronald P J Oude
authors.initials: RP
authors.lastname: Elferink
authors.forename: Hilde
authors.initials: H
authors.lastname: Rosing
authors.forename: Jos H
authors.initials: JH
authors.lastname: Beijnen
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 / Q000502:physiology*; D000284:Administration, Oral; D000818:Animals; D016026:Bone Marrow Transplantation; D002460:Cell Line; D002734:Chlorophyll / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000633:toxicity*; D002851:Chromatography, High Pressure Liquid; D017484:Dermatitis, Phototoxic / Q000209:etiology / Q000517:prevention & control*; D004032:Diet / Q000009:adverse effects; D004351:Drug Resistance / Q000235:genetics*; D005260:Female; D005333:Fetus / Q000378:metabolism; D005347:Fibroblasts / Q000378:metabolism; D020022:Genetic Predisposition to Disease; D000455:Medicago sativa / Q000009:adverse effects; D051379:Mice; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D015394:Molecular Structure; D009363:Neoplasm Proteins; D017319:Photosensitizing Agents / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000633:toxicity*; D017121:Porphyria, Hepatoerythropoietic / Q000235:genetics / Q000517:prevention & control* / Q000628:therapy; D011166:Porphyrins / Q000378:metabolism* / Q000493:pharmacokinetics; D011247:Pregnancy; D011524:Protoporphyrins / Q000097:blood* / Q000737:chemistry; D011828:Radiation Chimera; D019772:Topotecan / Q000493:pharmacokinetics / Q000633:toxicity
chemical_list: C116614:ABCG2 protein, human; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D009363:Neoplasm Proteins; D017319:Photosensitizing Agents; D011166:Porphyrins; D011524:Protoporphyrins; D002734:Chlorophyll; D019772:Topotecan; C028025:protoporphyrin IX; C032623:pheophorbide a