Abstract:
BACKGROUND & AIMS:The physiologic function of the efflux transporter Multidrug Resistance Protein 3 (MRP3) remains poorly defined. In vitro, MRP3 transports several glucuronidated compounds, but the compounds transported under physiologic conditions are unknown. Knowledge of the compounds transported by MRP3 in vivo would greatly contribute to the elucidation of the physiologic function of this transport protein. METHODS:We used targeted metabolomics to identify substrates of MRP3 in vivo. Liquid chromatography coupled to mass spectrometry was used to specifically screen in plasma and urine of mice for compounds containing a glucuronic acid moiety. RESULTS:We found that several highly abundant compounds containing a glucuronic acid moiety have a much lower abundance in plasma and urine of Mrp3((-/-)) than of wild-type mice. We identified these as phytoestrogen-glucuronides, and we show that MRP3 transports these compounds at high rates and with high affinity in vitro. CONCLUSIONS:We have identified the efflux transporter MRP3 as a major factor in the disposition of phytoestrogens, a class of compounds to which mammals are exposed via food of plant origin. Our targeted metabolomics approach is not restricted to MRP3 but applicable to many other transport proteins for which knockout mouse models are available. Similar screens could be developed for sulpho- and glutathione-conjugates, further increasing the potential of identifying new physiologic transporter substrates.
journal_name
Gastroenterologyjournal_title
Gastroenterologyauthors
van de Wetering K,Feddema W,Helms JB,Brouwers JF,Borst Pdoi
10.1053/j.gastro.2009.06.052subject
Has Abstractpub_date
2009-11-01 00:00:00pages
1725-35issue
5eissn
0016-5085issn
1528-0012pii
S0016-5085(09)01137-8journal_volume
137pub_type
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