Basolateral efflux mediated by multidrug resistance-associated protein 3 (Mrp3/Abcc3) facilitates intestinal absorption of folates in mouse.
OBJECTIVE
This study investigated the role of an ABC transporter, Mrp3/Abcc3 in intestinal folate absorption.


METHODS
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.


RESULTS
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.


CONCLUSIONS
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.
Laboratory of Molecular Pharmacokinetics, Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan.
Yoshiaki
Y
Kitamura
Hiroyuki
H
Kusuhara
Yuichi
Y
Sugiyama
D000818:Animals; D005492:Folic Acid / Q000097:blood / Q000493:pharmacokinetics*; D017353:Gene Deletion; D006710:Homocysteine / Q000097:blood / Q000493:pharmacokinetics; D007408:Intestinal Absorption; D002955:Leucovorin / Q000097:blood / Q000493:pharmacokinetics; D008297:Male; D051379:Mice; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000235:genetics / Q000378:metabolism*; D013763:Tetrahydrofolates / Q000097:blood / Q000493:pharmacokinetics; D014805:Vitamin B 12 / Q000097:blood / Q000493:pharmacokinetics
D005492:Folic Acid; D006710:Homocysteine; D002955:Leucovorin; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D013763:Tetrahydrofolates; D014805:Vitamin B 12; C114462:multidrug resistance-associated protein 3; C005984:5-methyltetrahydrofolate