Contamination of milk with drugs, pesticides and other xenotoxins can pose a major health risk to breast-fed infants and dairy consumers. Here we show that the multidrug transporter BCRP (encoded by ABCG2) is strongly induced in the mammary gland of mice, cows and humans during lactation and that it is responsible for the active secretion of clinically and toxicologically important substrates such as the dietary carcinogen PhIP, the anticancer drug topotecan and the antiulcerative cimetidine into mouse milk.

The breast cancer resistance protein (BCRP/ABCG2) is an ATP-binding cassette drug efflux transporter that extrudes xenotoxins from cells, mediating drug resistance and affecting the pharmacological behavior of many compounds. To study the interaction of human wild-type BCRP with steroid drugs, hormones, and the dietary carcinogen 2-amino-1-methyl-6-phenylimidazo(4,5-b)pyridine (PhIP), we expressed human BCRP in the murine MEF3.8 fibroblast cell line, which lacks Mdr1a/1b P-glycoprotein and Mrp1, and in the polarized epithelial MD-CKII cell line. We show that PhIP was efficiently transported by human BCRP in MDCKII-BCRP cells, as was found previously for murine Bcrp1. Furthermore, we show that six out of nine glucocorticoid drugs, corticosterone, and digoxin increased the accumulation of mitoxantrone in the MEF3.8-BCRP cell line, indicating inhibition of BCRP. In contrast, aldosterone and ursodeoxycholic acid had no significant effect on BCRP. The four most efficiently reversing glucocorticoid drugs (beclomethasone, 6␣-methylprednisolone, dexamethasone, and triamcinolone) and 17␤-estradiol showed a significantly reduced BCRPmediated transepithelial transport of PhIP by MDCKII-BCRP cells, with the highest reduction of PhIP transport ratio for beclomethasone (from 25.0 Ϯ 1.1 to 2.7 Ϯ 0.0). None of the tested endogenous steroids or synthetic glucocorticoids or digoxin, however, were transported substrates of BCRP. We also identified the H 2 -receptor antagonist drug cimetidine as a novel efficiently transported substrate for human BCRP and mouse Bcrp1. The generated BCRP-expressing cell lines thus provide valuable tools to study pharmacological and toxicological interactions mediated by BCRP and to identify new BCRP substrates.The breast cancer resistance protein (BCRP/ABCG2) belongs to the ATP-binding cassette (ABC) family of drug transporters. Human BCRP has been shown to mediate drug resistance through energy-dependent efflux of drug substrates without the need for glutathione. The range of drugs to which BCRP can confer resistance in tumor cell lines includes mi-

Nitrofurantoin is a commonly used urinary tract antibiotic prescribed to lactating woman. It is actively transported into human and rat milk by an unknown mechanism. Our group has demonstrated an important role of the breast cancer resistance protein (BCRP/ABCG2) in the secretion of xenotoxins into the milk. This ATP-binding cassette drug efflux transporter extrudes xenotoxins from cells in intestine, liver, mammary gland, and other organs, affecting the pharmacological and toxicological behavior of many compounds. We investigated whether Bcrp1 is involved in the pharmacokinetic profile of nitrofurantoin and its active secretion into the milk. Using polarized cell lines, we found that nitrofurantoin is efficiently transported by murine Bcrp1 and human BCRP. After oral administration of 10 mg/kg nitrofurantoin, the area under the plasma concentrationtime curve in Bcrp1 knockout mice was almost 4-fold higher than in wild-type mice (148.8 Ϯ 30.4 versus 37.5 Ϯ 6.8 min ⅐ g/ml); and after i.v. administration (5 mg/kg), 2-fold higher (139.2 Ϯ 22.0 versus 73.9 Ϯ 9.0 min ⅐ g/ml). Hepatobiliary excretion of nitrofurantoin was almost abolished in Bcrp1 knockout mice (9.6 Ϯ 3.2 versus 0.2 Ϯ 0.1% in wild-type and Bcrp1 knockout mice, respectively). The milk-to-plasma ratio of nitrofurantoin was almost 80 times higher in wild-type compared with Bcrp1 knockout lactating female mice (45.7 Ϯ 16.2 versus 0.6 Ϯ 0.1). Nitrofurantoin elimination via milk was quantitatively even higher than hepatobiliary elimination. We conclude that Bcrp1 is an important determinant for the bioavailability of nitrofurantoin and the main mechanism involved in its hepatobiliary excretion and secretion into the milk.Nitrofurantoin (1-[(5-nitro-2-furanyl)methylene]amino-2, 4-imidazolidinedione) is a nitrofuran-derivative antibacterial agent widely used in human and veterinary medicine. In humans, it is mainly used to treat urinary tract infections, which are among the most common bacterial infections. Patients receiving nitrofurantoin may have rare but serious side effects such as chronic liver disease, cholestatic hepatitis, or hemolytic anemia in glucose-6-phosphate dehydrogenase-deficient patients (Gerk et al., 2001a). Moreover, nitrofurantoin has been shown to be mutagenic and carcinogenic in animal models . Further knowledge about the factors affecting the pharmacokinetics of nitrofurantoin is therefore of clinical and toxicological importance.Nitrofurantoin is also prescribed to lactating women. Inadvertent transfer of drugs administered to the mother to milk is always a matter of concern in view of possible adverse effects in the infant. Nitrofurantoin is an inexpensive antibiotic that is often used in developing countries where formula feeding is not an alternative for breastfeeding . However, preliminary results from a continuous breeding study with mice revealed that chronic nitrofurantoin treatment of lactating mice resulted in decreased pup growth rate .It has been demonstrated that nitrofurantoin is actively transported into human a...

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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.