title: P-glycoprotein and multidrug resistance-associated protein 2 are oppositely altered in brain of rats with thioacetamide-induced acute liver failure.
abstract: BACKGROUND
  P-glycoprotein (P-GP) and multidrug resistance-associated protein 2 (MRP2) are involved in transport of many drugs across blood-brain barrier (BBB). The function and expression of P-GP and MRP2 may be modulated by different pathologies. Acute liver failure (ALF) was reported to impair BBB function, resulting in the increased BBB permeability.
  
  
  OBJECTIVE
  We investigated whether ALF altered function and expression of P-GP and MRP2 in brain of thioacetamide-induced ALF rats.
  
  
  METHODS
  ALF was induced by intraperitoneal injection of thioacetamide (300 mg/kg) for 2 days with a 24-h interval. The rats were used for experiments at 6, 12 and 24 h after the second administration. P-GP and MRP2 function in brain were determined using the brain-to-plasma ratios of corresponding substrates (rhodamine 123 and vincristine for P-GP; sulfobromophthalein and dinitrophenyl-S-glutathione for MRP2). Evans blue was used for examining the BBB integrity. Western blot was accomplished to determine P-GP and MRP2 protein expression.
  
  
  RESULTS
  The brain-to-plasma ratios of rhodamine 123 and vincristine were significantly increased in ALF-6 h rats and almost returned to normal levels in ALF-24 h rats, whereas those of sulfobromophthalein and dinitrophenyl-S-glutathione were decreased in all ALF rats. Western blot results showed that ALF decreased brain P-GP levels at 6 and 12 h, whereas increased MRP2 levels at 6, 12 and 24 h. No significant difference of Evans blue concentrations in brain was found among the four groups.
  
  
  CONCLUSIONS
  Function and expression of P-GP and MRP2 in brain of thioacetamide-induced ALF rats were oppositely altered.
authors.affiliation: Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing, China.
authors.forename: Shi
authors.initials: S
authors.lastname: Jin
authors.forename: Xin-Ting
authors.initials: XT
authors.lastname: Wang
authors.forename: Li
authors.initials: L
authors.lastname: Liu
authors.forename: Dan
authors.initials: D
authors.lastname: Yao
authors.forename: Can
authors.initials: C
authors.lastname: Liu
authors.forename: Mian
authors.initials: M
authors.lastname: Zhang
authors.forename: Hai-Fang
authors.initials: HF
authors.lastname: Guo
authors.forename: Xiao-Dong
authors.initials: XD
authors.lastname: Liu
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism*; D000818:Animals; D001812:Blood-Brain Barrier / Q000378:metabolism*; D015153:Blotting, Western; D001921:Brain / Q000378:metabolism*; D005070:Evans Blue; D007274:Injections, Intraperitoneal; D017114:Liver Failure, Acute / Q000139:chemically induced / Q000378:metabolism*; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000378:metabolism*; D010539:Permeability; D051381:Rats; D020112:Rhodamine 123 / Q000097:blood / Q000378:metabolism; D013853:Thioacetamide / Q000008:administration & dosage / Q000633:toxicity; D013997:Time Factors; D014750:Vincristine / Q000097:blood / Q000378:metabolism
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D005070:Evans Blue; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D020112:Rhodamine 123; D013853:Thioacetamide; D014750:Vincristine