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.

AIMS:

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: Shi Jin, Xin-Ting Wang, Li Liu, Dan Yao, Can Liu, Mian Zhang, Hai-Fang Guo, Xiao-Dong Liu
• Journal: Liver international : official journal of the International Association for the Study of the Liver (Liver Int) Vol. 33 Issue 2 Pg. 274-82 (Feb 2013) ISSN: 1478-3231 [Electronic] United States
• PMID: 22925079 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2012 John Wiley & Sons A/S.

Chemical References

• ATP Binding Cassette Transporter, Subfamily B, Member 1
• Multidrug Resistance-Associated Protein 2
• Multidrug Resistance-Associated Proteins
• Thioacetamide
• Rhodamine 123
• Evans Blue
• Vincristine

Topics

• ATP Binding Cassette Transporter, Subfamily B, Member 1 (metabolism)
• Animals
• Blood-Brain Barrier (metabolism)
• Blotting, Western
• Brain (metabolism)
• Evans Blue
• Injections, Intraperitoneal
• Liver Failure, Acute (chemically induced, metabolism)
• Multidrug Resistance-Associated Protein 2
• Multidrug Resistance-Associated Proteins (metabolism)
• Permeability
• Rats
• Rhodamine 123 (blood, metabolism)
• Thioacetamide (administration & dosage, toxicity)
• Time Factors
• Vincristine (blood, metabolism)