Breast cancer resistance protein (Bcrp1/Abcg2) reduces systemic exposure of the dietary carcinogens aflatoxin B1, IQ and Trp-P-1 but also mediates their secretion into breast milk.
The breast cancer resistance protein (BCRP/ABCG2) usually protects the body from a wide variety of environmental and dietary xenotoxins by reducing their net uptake from intestine and by increasing their hepatobiliary, intestinal and renal elimination. BCRP is also highly expressed in lactating mammary glands in mice, and this expression is conserved in cows and humans. As a result, BCRP substrates can be secreted into milk. We investigated whether different classes of dietary carcinogens are substrates of Bcrp1/BCRP and the implications for systemic exposure and breast milk contamination. Using polarized cell lines, we found that Bcrp1 transports the heterocyclic amines 2-amino-3-methylimidazo[4,5-f]quinoline (IQ) and 3-amino-1,4-dimethyl-5H-pyrido[4,3-b]indole (Trp-P-1) and the potent human hepatocarcinogen aflatoxin B1, and decreases their cellular accumulation up to 10-fold. In vivo pharmacokinetic studies showed that [14C]IQ, [14C]Trp-P-1 and [3H]aflatoxin B1 plasma levels were substantially lower in wild-type compared with Bcrp1-/- mice, after both oral and intravenous administration, demonstrating that Bcrp1 restricts systemic exposure to these carcinogens. Moreover, Bcrp1 mediates transfer of [14C]IQ, [14C]Trp-P-1 and [3H]aflatoxin into milk, with 3.4+/-0.6, 2.6+/-0.3 and 3.8+/-0.5-fold higher milk to plasma ratios, respectively, in lactating wild-type versus Bcrp1-/- mice. We have thus identified Bcrp1/BCRP as one of the molecular mechanisms by which heterocyclic amines and aflatoxin are transferred into milk, thereby posing a health risk to breast-fed infants and dairy consumers. Paradoxically, Bcrp1/BCRP appears to have both protective and adverse roles with respect to exposure to dietary carcinogens.
van Herwaarden
Antonius E
AE
Division of Experimental Therapy, The Netherlands Cancer Institute, 1066 CX Amsterdam, The Netherlands.
Wagenaar
Els
E
Karnekamp
Barbara
B
Merino
Gracia
G
Jonker
Johan W
JW
Schinkel
Alfred H
AH
D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000378:metabolism*; D016604:Aflatoxin B1 / Q000493:pharmacokinetics; D000818:Animals; D001682:Biological Availability; D001692:Biological Transport; D002243:Carbolines / Q000493:pharmacokinetics; D002250:Carbon Radioisotopes; D002273:Carcinogens / Q000493:pharmacokinetics*; D002478:Cells, Cultured; D004032:Diet; D004285:Dogs; D018432:Drug Resistance, Multiple; D005260:Female; D006801:Humans; D007093:Imidazoles / Q000493:pharmacokinetics; D007668:Kidney / Q000378:metabolism; D007774:Lactation; D051379:Mice; D018345:Mice, Knockout; D008895:Milk, Human / Q000378:metabolism*; D009363:Neoplasm Proteins / Q000378:metabolism*; D013552:Swine; D014018:Tissue Distribution
C116614:ABCG2 protein, human; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D002243:Carbolines; D002250:Carbon Radioisotopes; D002273:Carcinogens; D007093:Imidazoles; D009363:Neoplasm Proteins; D016604:Aflatoxin B1; C019132:3-amino-1,4-dimethyl-5H-pyrido(4,3-b)indole