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

Abstract

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.

Intestinal transporters for endogenic and pharmaceutical organic anions: the challenges of deriving in-vitro kinetic parameters for the prediction of clinically relevant drug–drug interactions

“…Chenodeoxycholate-3-sulfate [15] 131 Glycodeoxycholate [15] 2.0 Glycoursodeoxycholate [15] 4.1 Cholate [15,54] [15,54] 7.3/13 Deoxycholate [15,54] 5.2-13 Glycochenodeoxycholate [54] 2.0/2.9 Glychodeoxycholate [54] 2.4/5.4 Glycholate [54] 11/21 Taurochenodeoxycholate [15,54] 1.0-6.1 Taurocholate [15,54] 7.3-25 Taurodeoxycholate [15] 4.5-17 Taurourosdeoxycholate [15] 28 Ursodeoxycholate [15,54] 36 [60] Estrone [56] Bisantrene [67] Betamethasone [57] Riboflavin [68] Taurolithocholate sulfate [56] 37 a Cerivastatin [61] Cerivastain [61] 18 Uric acid [69] Vitamin K3 [ [70] Ciprofloxacin [71] Daunorubicin [56] 59 a Daunorubicin [67] Dexamethasone [57] Diclofenac [72] Diclofenac [72] 71-78 Dipyridamole [73] Digoxin [57] Doxorubicin [67,74] Dipyridamole [73] 6.4 a Enrofloxacin [75] Doxorubicin [56,76] Epirubicin [67] Fluvastatin [61] 5.4 Fluvastatin [61,62] Glibenclamide [77] 150 a Glibenclamide …”

Contribution of the drug transporter ABCG2 (breast cancer resistance protein) to resistance against anticancer nucleosides

“…ABCG2 transports a wide range of xenotoxins (reviewed in refs. 20 -22) and endogenous metabolites, such as riboflavin (23). It is present in the apical membrane of many tissues, such as the bile canalicular membrane of hepatocytes in the liver, the syncytiotrophoblasts in the placenta, the microvessel endothelium at the blood brain barrier, and the villi in the intestine (20 -23).…”

Functional expression and characterization in Xenopus laevis oocytes of the ABCG2 transporter derived from A549 human lung adenocarcinoma cells

“…These functions indicate a primary biological role for ABCG2 in the protection of these cells from xenobiotics. However, several other physiological functions have been observed, including the extrusion of porphyrins and/or porphyrin conjugates from hematopoietic cells, liver and harderian glands (26) as well as the secretion of vitamin B 2 and other vitamins into breast milk (27). Various compounds have been tested as inhibitors of the ABCG2 transporter, and estrogenic compounds, including estrone, several tamoxifen derivatives, phytoestrogens and flavonoids, have been shown to reverse ABCG2-mediated drug resistance (28).…”

“…Animal care and handling were carried out in accordance with the highest standards of institutional guidelines. X. laevis oocytes were prepared and maintained as previously described (27). Simultaneously, X. laevis oocytes were injected with 50 nl of water per oocyte (hereafter referred to as Control oocytes) or 50 nl of 1 µg/μl cRNA solution.…”