Basolateral Efflux Mediated by Multidrug Resistance-Associated Protein 3 (Mrp3/Abcc3) Facilitates Intestinal Absorption of Folates in Mouse

This study investigated the role of an ABC transporter, Mrp3/Abcc3 in intestinal folate absorption. Plasma concentrations of folic acid and leucovorin, given orally, were determined in wild-type and Mrp3 (-/-) mice. Mucosal-to-serosal transport was determined in the everted intestinal sacs. The plasma concentrations of endogenous 5-methyltetrahydrofolic acid, homocysteine and vitamin B-12, and mRNA levels of hepatic and intestinal folate metabolizing enzymes were compared between wild-type and Mrp3 (-/-) mice. C (max) and area-under plasma concentration-time curve of folic acid were 3.0- and 2.3-fold lower in Mrp3 (-/-) mice compared with wild-type mice, whereas the total body clearance was unchanged. Absorption of leucovorin was significantly delayed in Mrp3 (-/-) mice. Mucosal-to-serosal transport of folic acid and leucovorin was significantly decreased in the duodenum of Mrp3 (-/-) mice, where their PS (serosal) was decreased to 6.3 and 22% of that in wild-type mice, respectively. PS (serosal) of 5-methyltetrahydrofolic acid was moderately decreased in Mrp3 (-/-) mice. There was no obvious abnormality in folate homeostasis in Mrp3 (-/-) mice. Mrp3 accounts for the serosal efflux of folic acid and leucovorin, while it makes a moderate contribution to the serosal efflux of 5-methyltetrahydrofolic acid in mice. Mrp3 dysfunction does not disrupt folate homeostasis in mouse.