Abstract
This study investigated alterations in the function and expression of P-glycoprotein (P-GP), breast cancer resistance protein (BCRP), and multidrug resistance-associated protein 2 (MRP2) at the blood–brain barrier (BBB) of acute liver failure (ALF) mice and its clinical significance. ALF mice were developed using intraperitoneal injection of thioacetamide. P-GP, BCRP, and MRP2 functions were determined by measuring the ratios of brain-to-plasma concentration of rhodamine 123, prazosin, and dinitrophenyl-S-glutathione, respectively. The mRNA and proteins expression levels of P-GP, BCRP, and MRP2 were evaluated with quantitative real-time PCR and western blot, respectively. MDCK-MDR1 and HCMEC/D3 cells were used to document the effects of the abnormally altered components in serum of ALF mice on the function and expression of P-GP. The clinical significance of alteration in P-GP function and expression was investigated by determining the distribution of the P-GP substrate phenobarbital (60 mg/kg, intravenous administration) in the brain and loss of righting reflex (LORR) induced by the drug (100 mg/kg). The results showed that ALF significantly downregulated the function and expression of both P-GP and BCRP, but increased the function and expression of MRP2 in the brain of mice. Cell study showed that increased chenodeoxycholic acid may be a reason behind the downregulated P-GP function and expression. Compared with control mice, ALF mice showed a significantly higher brain concentration of phenobarbital and higher brain-to-plasma concentration ratios. In accordance, ALF mice showed a significantly larger duration of LORR and shorter latency time of LORR by phenobarbital, inferring the enhanced pharmacological effect of phenobarbital on the central nervous system (CNS). In conclusion, the function and expression of P-GP and BCRP decreased, while the function and expression of MRP2 increased in the brain of ALF mice. The attenuated function and expression of P-GP at the BBB might enhance phenobarbital distribution in the brain and increase phenobarbital efficacy on the CNS of ALF mice.
Highlights
Acute liver failure (ALF) is often associated with serious neurological complications and is responsible for mortality such as encephalopathy, brain edema, and hepatic coma
The levels of GSH and CAT were significantly decreased, while the levels of MDA were increased in the brain of ALF mice compared with those in control mice, which indicated that oxidative stress had occurred in the brain of ALF mice
The results showed that the plasma concentration of rhodamine 123 was significantly increased in ALF mice, contrarily, plasma concentration of prazosin was significantly decreased in ALF mice compared with control mice
Summary
Acute liver failure (ALF) is often associated with serious neurological complications and is responsible for mortality such as encephalopathy, brain edema, and hepatic coma. This is likely due to the accumulation of disordered neuroactive or neurotoxic components in the brain (Villano et al, 2012; Butterworth, 2015; Hadjihambi et al, 2017). The alterations in the function and expression of these ABC efflux transporters are important factors contributing to BBB dysfunction under a disease status (Jing et al, 2010; Yao et al, 2012; Jin et al, 2013; Liu and Liu, 2014)
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