Do multidrug resistance-associated protein-1 and -2 play any role in the elimination of estradiol-17 beta-glucuronide and 2,4-dinitrophenyl-S-glutathione across the blood-cerebrospinal fluid barrier?
The purpose of this study was to examine the role of multidrug resistance-associated protein-1 and -2 (Mrp1 and Mrp2) in the efflux transport of organic anions across the blood-cerebrospinal fluid (CSF) barrier. The CSF concentration of estradiol-17beta-glucuronide (E(2)17betaG) and 2,4-dinitrophenyl-S-glutathione (DNP-SG) in the CSF after intracerebroventricular and intravenous injection were compared between wild-type and Mrp1 gene knockout mice. There was no significant difference in the apparent CSF elimination rate constants of E(2)17betaG (0.158 and 0.145 min(-1)) and DNP-SG (0.116 and 0.0779 min(-1)) between wild-type and Mrp1 knockout mice, respectively. After intravenous administration of E(2)17betaG, its brain-to-serum and CSF-to-serum concentration ratios in Mrp1 knockout mice were not significantly different from those in the wild-type. Results from in vivo and in vitro studies using Eisai hyperbilirubinemic rats, in which Mrp2 is hereditarily deficient, were similar to those using normal rats. Quantitative polymerase chain reaction (PCR) showed that the expression level of Mrp4 and Mrp5 was several times higher than that of Mrp1, whereas the expression levels of Mrp2, Mrp3, and Mrp6 were negligible or low. Therefore, Mrp4 and Mrp5 may contribute to the efflux transport of E(2)17betaG and DNP-SG from the CSF.
Lee
Young-Joo
YJ
Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan.
Kusuhara
Hiroyuki
H
Sugiyama
Yuichi
Y
D018435:ATP Binding Cassette Transporter, Subfamily B / Q000172:deficiency / Q000502:physiology*; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000172:deficiency / Q000502:physiology*; D018528:ATP-Binding Cassette Transporters / Q000502:physiology*; D000818:Animals; D001812:Blood-Brain Barrier / Q000378:metabolism*; D004958:Estradiol / Q000031:analogs & derivatives* / Q000097:blood / Q000134:cerebrospinal fluid*; D005978:Glutathione / Q000031:analogs & derivatives* / Q000097:blood / Q000134:cerebrospinal fluid*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D017207:Rats, Sprague-Dawley
D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D018528:ATP-Binding Cassette Transporters; D012333:RNA, Messenger; C025483:estradiol-17 beta-glucuronide; C030190:S-(2,4-dinitrophenyl)glutathione; D004958:Estradiol; C095122:multidrug resistance protein 3; D005978:Glutathione