Acute liver failure impairs function and expression of breast cancer‐resistant protein (BCRP) at rat blood–brain barrier partly via ammonia‐ROS‐ERK1/2 activation

Abstract

We once reported that P-glycoprotein (P-GP) and multidrug resistance-associated protein 2 (MRP2) were oppositely regulated at the blood-brain barrier (BBB) of thioacetamideinduced acute liver failure (ALF) rats. This study aimed to investigate whether ALF affected function and expression of breast cancer-resistant protein (BCRP) at the BBB of rats and the role of ammonia in the regulation. ALF rats were developed by intraperitoneal (i.p.) injection of thioacetamide (300 mg/kg) for 2 days. Hyperammonemic rats were developed by NH 4 Ac (i.p. 4.5 mmol/kg). BCRP function and expression were measured by brain distribution of specific substrates (prazosin and methotrexate) and western blot, respectively. MDCK-BCRP cells and primarily cultured rat brain microvessel endothelial cells (rBMECs) were employed to investigate possible mechanisms through which ammonia regulated BCRP function and expression. The results showed that both ALF and hyperammonemia significantly weakened function and expression of BCRP in the brain of rats. The function and expression of BCRP in MDCK-BCRP cells and rBMECs were strikingly decreased after exposure to NH 4 Cl and H 2 O 2 , accompanied by remarkable increases in the levels of phosphorylated ERK1/2 and reactive oxygen species (ROS). The altered BCRP expression and function by ammonia and H 2 O 2 were restored by ROS scavenger N-acetylcysteine and ERK1/2 inhibitor U0126. Markedly increased levels of ERK1/2 phosphorylation and ROS were found in the brains of ALF rats and hyperammonemic rats. All above results indicated ALF down-regulated expression and function of BCRP at BBB of rats partly via hyperammonemia. Activation of ROS-mediated ERK1/2 phosphorylation may be one of the reasons that ammonia impaired BCRP expression and function at the BBB. Keywords: acute liver failure, blood-brain barrier, breast cancer resistance protein, hyperammonemia, reactive oxygen species.

Leaky brain in neurological and psychiatric disorders: Drivers and consequences

“…Acute hepatic failure is associated with hyperammonaemia, which in turn is associated with neuroinflammation and neuropsychiatric presentations, such as hepatic encephalopathy (Albrecht and Norenberg, 2006;Ott and Vilstrup, Australian & New Zealand Journal of Psychiatry, 52(10) 2014). The ammonia crosses into BMECs, where it adversely affects the functioning and expression of breast cancer resistance protein (BCRP) by activation of ammonia-ROS-extracellular-regulated protein kinase-1/2 (ERK1/2) (Li et al, 2016c). Murine experimentation has recently shown that NAC (a ROS scavenger) restores the functioning and expression of BCRP (Li et al, 2016c).…”

“…The ammonia crosses into BMECs, where it adversely affects the functioning and expression of breast cancer resistance protein (BCRP) by activation of ammonia-ROS-extracellular-regulated protein kinase-1/2 (ERK1/2) (Li et al, 2016c). Murine experimentation has recently shown that NAC (a ROS scavenger) restores the functioning and expression of BCRP (Li et al, 2016c).…”

Effect of Oxidative Stress on ABC Transporters: Contribution to Epilepsy Pharmacoresistance

“…NF-κB activation was found responsible for transporter upregulation. Further, another recent report from the same group, concluded that ROS mediated ERK1/2 phosphorylation was involved in the downregulating BCRP expression in rat BBB [ 72 ].…”

Acute liver failure enhances oral plasma exposure of zidovudine in rats by downregulation of hepatic UGT2B7 and intestinal P-gp

“…Our previous studies have verified that hyperammonemia increases the function and expression of P-gp at the bloodbrain barrier by activating the NF-κB pathway [35] and that ALF impairs the function and expression of BCRP at the bloodbrain barrier partly by activating the ammonia-ROS-ERK1/2 pathway [23] . These results indicate tissue-specific alterations in the expression and function of P-gp and BCRP in ALF rats.…”

“…These membranes act as defenders against numerous exogenous and endogenous substances. Our previous study has also indicated that acute liver failure (ALF) impairs the function and expression of P-gp and BCRP at the blood-brain barrier in rats, thus resulting in increased brain distributions of rhodamine 123 and prazosin [23,24] . However, information on intestinal P-gp and BCRP functions and expression under liver failure status is lacking.…”