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.

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