title: Opposite regulation of hepatic breast cancer resistance protein in type 1 and 2 diabetes mellitus.
abstract: Previous studies on diabetes have reported controversial results with regard to transporters in liver. The present study aimed to explore changes in hepatic breast cancer resistance protein (BCRP) expression and functions, as well as the possible underlying mechanisms, in type 2 diabetic patients, type 1 (streptozotocin-induced), and type 2 (Goto Kakizaki) diabetic rats. Protein and mRNA levels of human (h) and rat (r) BCRP were investigated using Western blot and quantitative polymerase chain reaction analyses. Functions of liver rBCRP were evaluated using rosuvastatin. Sandwich cultured rat hepatocytes (SCRH) were cultured with d-glucose, insulin, or oleic acid for 72 h, and rBCRP mRNA was detected. The effect of oleic acid on rBCRP function in SCRH was also investigated using rosuvastatin. Results showed that liver rBCRP mRNA levels decreased to 20% in type 1 diabetic rats, whereas that in diabetic patients and GK rats significantly increased threefold and twentyfold, respectively. No changes were observed in h/rBCRP protein levels of type 2 diabetic patients and GK rats. The functions of rBCRP significantly declined in type 1 diabetic rats but showed no significant changes in GK rats. The data from SCRH indicated that d-glucose decreased rBCRP mRNA level to 60%. Oleic acid increased rBCRP mRNA in SCRH by approximately eightfold but decreased rBCRP function to 50%. Therefore, h/rBCRP expression and functions were oppositely regulated in type 1 and type 2 diabetes mellitus subjects. Alternations in d-glucose, insulin, and free fatty acid levels in plasma might contribute to the changes in h/rBCRP expression and functions.
authors.affiliation: Center for Drug Safety Evaluations and Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China; Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing 210009, China.
authors.forename: Lei
authors.initials: L
authors.lastname: He
authors.affiliation: Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai 200438, China.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Yang
authors.affiliation: Center for Drug Safety Evaluations and Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China; Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing 210009, China.
authors.forename: Cen
authors.initials: C
authors.lastname: Guo
authors.affiliation: Center for Drug Safety Evaluations and Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.
authors.forename: Dan
authors.initials: D
authors.lastname: Yao
authors.affiliation: Center for Drug Safety Evaluations and Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.
authors.forename: Hui-hui
authors.initials: HH
authors.lastname: Liu
authors.affiliation: Center for Drug Safety Evaluations and Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.
authors.forename: Jing-jing
authors.initials: JJ
authors.lastname: Sheng
authors.affiliation: Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai 200438, China.
authors.forename: Wei-ping
authors.initials: WP
authors.lastname: Zhou
authors.affiliation: Center for Drug Safety Evaluations and Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.
authors.forename: Jin
authors.initials: J
authors.lastname: Ren
authors.affiliation: Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing 210009, China. Electronic address: xdliu@cpu.edu.cn.
authors.forename: Xiao-dong
authors.initials: XD
authors.lastname: Liu
authors.affiliation: Center for Drug Safety Evaluations and Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China. Electronic address: gypan@cdser.simm.ac.cn.
authors.forename: Guo-yu
authors.initials: GY
authors.lastname: Pan
mesh_terms: D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism*; D000328:Adult; D000368:Aged; D000818:Animals; D001646:Bile / Q000737:chemistry; D002478:Cells, Cultured; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism*; D003922:Diabetes Mellitus, Type 1 / Q000378:metabolism*; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism*; D005260:Female; D005464:Fluorobenzenes / Q000097:blood / Q000493:pharmacokinetics; D005947:Glucose / Q000494:pharmacology; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000097:blood / Q000493:pharmacokinetics; D007328:Insulin / Q000494:pharmacology; D008099:Liver / Q000378:metabolism; D008113:Liver Neoplasms / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D019301:Oleic Acid / Q000494:pharmacology; D011743:Pyrimidines / Q000097:blood / Q000493:pharmacokinetics; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D000068718:Rosuvastatin Calcium; D013449:Sulfonamides / Q000097:blood / Q000493:pharmacokinetics
chemical_list: C116614:ABCG2 protein, human; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; C489249:Abcg2 protein, rat; D005464:Fluorobenzenes; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007328:Insulin; D009363:Neoplasm Proteins; D011743:Pyrimidines; D012333:RNA, Messenger; D013449:Sulfonamides; D019301:Oleic Acid; D000068718:Rosuvastatin Calcium; D005947:Glucose
keywords: Breast cancer resistant protein; D-glucose (PubChem CID: 5793); Diabetes; Oleic acid (PubChem CID: 445639); Rosuvastatin calcium (PubChem CID: 5282455); Sandwich cultured rat hepatocytes