The breast cancer resistance protein protects against a major chlorophyll-derived dietary phototoxin and protoporphyria

Johan W Jonker; Marije Buitelaar; Els Wagenaar; Martin A Van Der Valk; George L Scheffer; Rik J Scheper; Torsten Plosch; Folkert Kuipers; Ronald P J Oude Elferink; Hilde Rosing; Jos H Beijnen; Alfred H Schinkel

doi:10.1073/pnas.202607599

The breast cancer resistance protein protects against a major chlorophyll-derived dietary phototoxin and protoporphyria

Proc Natl Acad Sci U S A. 2002 Nov 26;99(24):15649-54. doi: 10.1073/pnas.202607599. Epub 2002 Nov 12.

Authors

Johan W Jonker¹, Marije Buitelaar, Els Wagenaar, Martin A Van Der Valk, George L Scheffer, Rik J Scheper, Torsten Plosch, Folkert Kuipers, Ronald P J Oude Elferink, Hilde Rosing, Jos H Beijnen, Alfred H Schinkel

Affiliation

¹ Division of Experimental Therapy, The Netherlands Cancer Institute, 1066 CX Amsterdam, The Netherlands.

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

ATP Binding Cassette Transporter, Subfamily G, Member 2
ATP-Binding Cassette Transporters / genetics
ATP-Binding Cassette Transporters / physiology*
Administration, Oral
Animals
Bone Marrow Transplantation
Cell Line
Chlorophyll / administration & dosage
Chlorophyll / analogs & derivatives*
Chlorophyll / pharmacokinetics
Chlorophyll / toxicity*
Chromatography, High Pressure Liquid
Dermatitis, Phototoxic / etiology
Dermatitis, Phototoxic / prevention & control*
Diet / adverse effects
Drug Resistance / genetics*
Female
Fetus / metabolism
Fibroblasts / metabolism
Genetic Predisposition to Disease
Medicago sativa / adverse effects
Mice
Mice, Inbred Strains
Mice, Knockout
Molecular Structure
Neoplasm Proteins*
Photosensitizing Agents / administration & dosage
Photosensitizing Agents / pharmacokinetics
Photosensitizing Agents / toxicity*
Porphyria, Hepatoerythropoietic / genetics
Porphyria, Hepatoerythropoietic / prevention & control*
Porphyria, Hepatoerythropoietic / therapy
Porphyrins / metabolism*
Porphyrins / pharmacokinetics
Pregnancy
Protoporphyrins / blood*
Protoporphyrins / chemistry
Radiation Chimera
Topotecan / pharmacokinetics
Topotecan / toxicity

Substances

ABCG2 protein, human
ATP Binding Cassette Transporter, Subfamily G, Member 2
ATP-Binding Cassette Transporters
Neoplasm Proteins
Photosensitizing Agents
Porphyrins
Protoporphyrins
Chlorophyll
Topotecan
protoporphyrin IX
pheophorbide a