Cadmium inhibits ABCG2 transporter function in BeWo choriocarcinoma cells and MCF-7 cells overexpressing ABCG2.
Heavy metals such as cadmium, lead and methylmercury are known to be neurotoxic to developing fetus. ABCG2 which is an efflux transporter located in the maternal facing membranes of human placenta protects fetus from xenobiotics by transferring compounds from syncytiotrophoblast to maternal circulation. The aim of this study was to clarify whether heavy metal compounds (CdCl(2), PbCl(2) and MeHgCl) affect the expression and function of ABCG2 transporter in human placental BeWo choriocarcinoma cells. The expression of ABCG2 was determined by immunoblotting and RT-PCR. The functional activity of ABCG2 was evaluated by measuring the efflux of two known ABCG2 substrates: fluorescent mitoxantrone and (14)C-labeled food carcinogen PhIP. According to MTT assay all compounds were cytotoxic as expected (MeHgCl > CdCl(2) > PbCl(2)). CdCl(2) inhibited the efflux of mitoxantrone and (14)C-PhIP suggesting inhibition of ABCG2 transporter function. PbCl(2) had no effect on mitoxantrone efflux. Because of high toxicity, the inhibitory potency of MeHgCl was not tested. According to protein data these heavy metals did not affect ABCG2 transporter protein expression. Also, the expression of ABCC1, ABCC2 or ABCG2 mRNA were not affected by heavy metals. In conclusion, although the studied metal salts did not affect mRNA or protein expression of ABCG2, CdCl(2) inhibited its function. Further studies to evaluate whether this leads to elevated placental transfer of ABCG2 substrates are needed.
Department of Pharmacology and Toxicology, Institute of Biomedicine, University of Oulu, P.O. Box 5000, 90014 Oulu, Finland.
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Kummu
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Sieppi
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Wallin
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Rautio
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Vähäkangas
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Myllynen
D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D019256:Cadmium Chloride / Q000633:toxicity*; D045744:Cell Line, Tumor; D002822:Choriocarcinoma / Q000378:metabolism; D005260:Female; D006801:Humans; D007093:Imidazoles / Q000378:metabolism / Q000494:pharmacology; D008942:Mitoxantrone / Q000378:metabolism; D000089762:Multidrug Resistance-Associated Protein 2; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D011247:Pregnancy
C000715087:ABCC2 protein, human; C116614:ABCG2 protein, human; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D007093:Imidazoles; D000089762:Multidrug Resistance-Associated Protein 2; D009363:Neoplasm Proteins; C049584:2-amino-1-methyl-6-phenylimidazo(4,5-b)pyridine; D008942:Mitoxantrone; D019256:Cadmium Chloride