Multidrug transporter ABCG2/breast cancer resistance protein secretes riboflavin (vitamin B2) into milk.
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 B(2)) 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 B(2) 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.
van Herwaarden
Antonius E
AE
Division of Experimental Therapy, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands. a.schinkel@nki.nl.
Wagenaar
Els
E
Merino
Gracia
G
Jonker
Johan W
JW
Rosing
Hilde
H
Beijnen
Jos H
JH
Schinkel
Alfred H
AH
D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000378:metabolism*; D000818:Animals; D001692:Biological Transport; D001710:Biotin / Q000032:analysis; D004285:Dogs; D005260:Female; D005486:Flavin Mononucleotide / Q000032:analysis / Q000097:blood; D005182:Flavin-Adenine Dinucleotide / Q000032:analysis / Q000097:blood; D007774:Lactation; D008297:Male; D008321:Mammary Glands, Animal / Q000378:metabolism; D051379:Mice; D008892:Milk / Q000737:chemistry* / Q000378:metabolism*; D009363:Neoplasm Proteins / Q000378:metabolism; D012256:Riboflavin / Q000032:analysis / Q000737:chemistry / Q000378:metabolism* / Q000493:pharmacokinetics; D012727:Sex Characteristics; D014018:Tissue Distribution; D014316:Tritium
C116614:ABCG2 protein, human; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; C501412:Abcg2 protein, mouse; D009363:Neoplasm Proteins; D014316:Tritium; D005182:Flavin-Adenine Dinucleotide; D001710:Biotin; D005486:Flavin Mononucleotide; D012256:Riboflavin