Document Detail


The breast cancer resistance protein protects against a major chlorophyll-derived dietary phototoxin and protoporphyria.
MedLine Citation:
PMID:  12429862     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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:
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
Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2002-11-12
Journal Detail:
Title:  Proceedings of the National Academy of Sciences of the United States of America     Volume:  99     ISSN:  0027-8424     ISO Abbreviation:  Proc. Natl. Acad. Sci. U.S.A.     Publication Date:  2002 Nov 
Date Detail:
Created Date:  2002-11-27     Completed Date:  2003-01-14     Revised Date:  2013-04-18    
Medline Journal Info:
Nlm Unique ID:  7505876     Medline TA:  Proc Natl Acad Sci U S A     Country:  United States    
Other Details:
Languages:  eng     Pagination:  15649-54     Citation Subset:  IM    
Affiliation:
Division of Experimental Therapy, The Netherlands Cancer Institute, 1066 CX Amsterdam, The Netherlands.
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MeSH Terms
Descriptor/Qualifier:
ATP-Binding Cassette Transporters / genetics,  physiology*
Administration, Oral
Animals
Bone Marrow Transplantation
Cell Line
Chlorophyll / administration & dosage,  analogs & derivatives*,  pharmacokinetics,  toxicity*
Chromatography, High Pressure Liquid
Dermatitis, Phototoxic / etiology,  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,  pharmacokinetics,  toxicity*
Porphyria, Hepatoerythropoietic / genetics,  prevention & control*,  therapy
Porphyrins / metabolism*,  pharmacokinetics
Pregnancy
Protoporphyrins / blood*,  chemistry
Radiation Chimera
Topotecan / pharmacokinetics,  toxicity
Chemical
Reg. No./Substance:
0/ABCG2 protein, human; 0/Neoplasm Proteins; 0/Photosensitizing Agents; 0/Porphyrins; 0/Protoporphyrins; 123948-87-8/Topotecan; 1406-65-1/Chlorophyll; 15664-29-6/pheophorbide a; 553-12-8/protoporphyrin IX
Comments/Corrections

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