Partial hepatectomy aggravates cyclosporin A-induced neurotoxicity by lowering the function of the blood–brain barrier in mice

P‐glycoprotein and multidrug resistance‐associated protein 2 are oppositely altered in brain of rats with thioacetamide‐induced acute liver failure

“…The main findings were that the function of P-GP and MRP2 in brain of ALF rats were oppositely altered and the alterations induced by ALF were partly or almost totally restored to the normal levels at 12 and 24 h after the last administration of thioacetamide. Similar changes of P-GP function were also observed in ALF mice induced by partial hepatectomy (11) and CCl 4 (12). The function of P-GP and MRP2 were in line with alterations of their respective expression, an indication that changes of P-GP and MRP2 protein levels partly contributed to the altered function of P-GP and MRP2 in brain of ALF rats.…”

“…Huang et al reported that brain P-GP function in rats of CCl 4 -induced ALF was suppressed without changes of P-GP protein levels (12). In addition, the accumulation of rhodamine 123 in mouse brain endothelial cells (MBEC4) pre-incubated with plasma obtained from hepatectomized mice was higher than that in MBEC4 pre-incubated with sham-operated mice, even though there was no significant difference in the expression levels of mdr1a and mdr1b mRNA in cerebral capillaries between partial hepatectomized and sham-operated mice (11). These findings suggested that in addition to the expression levels, other factors such as corticosterone (12) and inflammatory cytokines (29) may also be involved in the altered function of these transporters.…”

Hyperammonemia enhances the function and expression of P‐glycoprotein and Mrp2 at the blood–brain barrier through NF‐κB

“…Accumulating evidence has implied that liver failure induces functional disturbances of the CNS characterized by disturbance of both cognitive and motor functions starting with personality changes progressing through more severe cognitive and motor symptoms to stupor and coma (Lemberg and Fern andez 2009). In addition to neurocognitive disorder, recent studies in our own and other laboratories have shown that liver failure affects delivery of some compounds into brain via altering the function and expression of P-gp and Mrp2 at the BBB (Huang et al 2001;Yamauchi et al 2011;Jin et al 2012Jin et al , 2013. Ammonia has been strongly implicated as the most important factor in the pathogenesis of CNS disorders caused by liver failure (Albrecht and Jones 1999).…”

“…; Yamauchi et al . ). Our previous studies also demonstrated that both function and expression of P‐gp and Mrp2 were altered remarkably in brain of rats with thioacetamide‐induced acute and chronic liver failure, leading to marked alterations in delivery of substrate drugs into brain (Jin et al .…”

“…Alterations in function and expression of these ABC transporters at the BBB may affect the brain penetration of a range of important drugs, resulting in alterations of their pharmacological effects on central nervous system (CNS), even neurotoxicity. Accumulating studies reported that the function of P-gp and Mrp2 at the BBB could be affected by various disease states, including hypoxia-ischaemia , epilepsy (Jing et al 2010;Yao et al 2012) and diabetes mellitus , as well as liver failure (Huang et al 2001;Yamauchi et al 2011). Our previous studies also demonstrated that both function and expression of P-gp and Mrp2 were altered remarkably in brain of rats with thioacetamide-induced acute and chronic liver failure, leading to marked alterations in delivery of substrate drugs into brain (Jin et al , 2013.…”