title: Effect of methotrexate treatment on expression levels of organic anion transporter polypeptide 2, P-glycoprotein and bile salt export pump in rats.
abstract: High-dose methotrexate (HDMTX) chemotherapy with leucovorin (LV) rescue has been used as a therapeutic strategy in oncology since the 1970s. Adverse reactions following extension of methotrexate (MTX) elimination are a crucial problem in HDMTX chemotherapy. MTX is a substrate for drug transporters, which are multidrug resistance protein 2 (Mrp2), organic anion transporter polypeptide 2 (Oatp2) and other transporters. We previously reported that MTX treatment downregulated the expression level of Mrp2 in rats. Here we examined the effect of MTX treatment on the expression of Oatp2, P-glycoprotein (P-gp) and bile salt export pump (Bsep) in rats. MTX was single-injected intraperitoneally at a dose of 150 mg/kg, and Western blot analysis was performed. The levels of Oatp2, P-gp and Bsep in the liver on day 4 after treatment were downregulated to 36.3 +/- 6.9%, 51.5 +/- 5.2% and 61.8 +/- 5.5% (mean +/- S.E.M.) of controls, respectively. Expression levels of P-gp in the kidney and ileum were also downregulated to 38.5 +/- 1.6% and 16.2 +/- 1.6% of controls, respectively. These effects of MTX were partially recovered by LV, which rescues normal cells from MTX toxicity. In conclusion, the result indicates that MTX treatment downregulates expression levels of Oatp2, P-gp and Bsep.
authors.affiliation: Department of Clinical Pharmacy, Kagoshima University Medical and Dental Hospital, Kagoshima University, USA.
authors.forename: Yoshihiko
authors.initials: Y
authors.lastname: Shibayama
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Takeda
authors.forename: Katsushi
authors.initials: K
authors.lastname: Yamada
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000096:biosynthesis*; D000074020:ATP Binding Cassette Transporter, Subfamily B, Member 11; D018528:ATP-Binding Cassette Transporters / Q000096:biosynthesis*; D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000633:toxicity*; D005493:Folic Acid Antagonists / Q000494:pharmacology*; D008297:Male; D008727:Methotrexate / Q000633:toxicity*; D027361:Organic Anion Transporters / Q000096:biosynthesis*; D051381:Rats; D017208:Rats, Wistar
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000074020:ATP Binding Cassette Transporter, Subfamily B, Member 11; D018528:ATP-Binding Cassette Transporters; C490548:Abcb11 protein, rat; D000964:Antimetabolites, Antineoplastic; D005493:Folic Acid Antagonists; D027361:Organic Anion Transporters; C503597:Slco1a4 protein, rat; D008727:Methotrexate