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Molecular and Cellular Biology, February 2007, p. 1247-1253, Vol. 27, No. 4
0270-7306/07/$08.00+0     doi:10.1128/MCB.01621-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Multidrug Transporter ABCG2/Breast Cancer Resistance Protein Secretes Riboflavin (Vitamin B₂) into Milk

Antonius E. van Herwaarden,¹ Els Wagenaar,¹ Gracia Merino,^1, Johan W. Jonker,^1, Hilde Rosing,² Jos H. Beijnen,² and Alfred H. Schinkel^1*

Division of Experimental Therapy, The Netherlands Cancer Institute, 1066 CX Amsterdam, The Netherlands,¹ Department of Pharmacy and Pharmacology, Slotervaart Hospital, 1066 EC Amsterdam, The Netherlands²

Received 31 August 2006/ Returned for modification 13 November 2006/ Accepted 27 November 2006

The multidrug transporter breast cancer resistance protein (BCRP/ABCG2) is strongly induced in the mammary gland during pregnancy and lactation. We here demonstrate that BCRP is responsible for pumping riboflavin (vitamin B₂) into milk, thus supplying the young with this important nutrient. In Bcrp1^–/– mice, milk secretion of riboflavin was reduced >60-fold compared to that in wild-type mice. Yet, under laboratory conditions, Bcrp1^–/– pups showed no riboflavin deficiency due to concomitant milk secretion of its cofactor flavin adenine dinucleotide, which was not affected. Thus, two independent secretion mechanisms supply vitamin B₂ equivalents to milk. BCRP is the first active riboflavin efflux transporter identified in mammals and the first transporter shown to concentrate a vitamin into milk. BCRP activity elsewhere in the body protects against xenotoxins by reducing their absorption and mediating their excretion. Indeed, Bcrp1 activity increased excretion of riboflavin into the intestine and decreased its systemic availability in adult mice. Surprisingly, the paradoxical dual utilization of BCRP as a xenotoxin and a riboflavin pump is evolutionarily conserved among mammals as diverse as mice and humans. This study establishes the principle that an ABC transporter can transport a vitamin into milk and raises the possibility that other vitamins and nutrients are likewise secreted into milk by ABC transporters.

Published ahead of print on 4 December 2006.

Present address: Department of Physiology, Faculty of Veterinary Medicine, University of Leon, Campus de Vegazana s/n, 24071 León, Spain.

Present address: The Salk Institute for Biological Studies, Howard Hughes Medical Institute, 10010 N. Torrey Pines Rd., La Jolla, CA 92037.

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