Bile duct ligation enhances AZT CNS toxicity partly by impairing the expression and function of BCRP in rat brain

Qin, Yuanyuan; Xu, Ping; Wu, Tong; Qian, Chao-qun; Fan, Yilin; Gen, Dong-hao; Zhu, Liang; Kong, Weimin; Yang, Hanyu; Xu, Feng; Yang, Yiting; Liu, Li; Liu, Xiaodong

doi:10.1038/s41401-019-0242-8

Cited by 10 publications

(13 citation statements)

References 42 publications

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“…Liver injury has been demonstrated to alter the expressions and functions of ABC transporters at the blood–brain barrier (BBB). For example, liver injury induced by BDL has been reported to suppress function and expression of Bcrp but enhance the function and expression of P-gp at the BBB of rats [ 18 , 19 , 20 ]. Acute liver injury induced by thioacetamide significantly decreased the expressions and functions of P-gp and Bcrp but increased the expression and function of Mrp2 at the BBB of rats [ 21 , 22 ].…”

Section: Introductionmentioning

confidence: 99%

Bile Duct Ligation Impairs Function and Expression of Mrp1 at Rat Blood–Retinal Barrier via Bilirubin-Induced P38 MAPK Pathway Activations

Yang

Lin

et al. 2022

IJMS

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Liver injury is often associated with hepatic retinopathy, resulting from accumulation of retinal toxins due to blood–retinal barrier (BRB) dysfunction. Retinal pigment epithelium highly expresses MRP1/Mrp1. We aimed to investigate whether liver injury affects the function and expression of retinal Mrp1 using bile duct ligation (BDL) rats. Retinal distributions of fluorescein and 2,4-dinitrophenyl-S-glutathione were used for assessing Mrp1 function. BDL significantly increased distributions of the two substrates and bilirubin, downregulated Mrp1 protein, and upregulated phosphorylation of p38 and MK2 in the retina. BDL neither affected the retinal distribution of FITC-dextran nor expressions of ZO-1 and claudin-5, demonstrating intact BRB integrity. In ARPE-19 cells, BDL rat serum or bilirubin decreased MRP1 expression and enhanced p38 and MK2 phosphorylation. Both inhibiting and silencing p38 significantly reversed the bilirubin- and anisomycin-induced decreases in MRP1 protein. Apparent permeability coefficients of fluorescein in the A-to-B direction (Papp, A-to-B) across the ARPE-19 monolayer were greater than Papp, B-to-A. MK571 or bilirubin significantly decreased Papp, A-to-B of fluorescein. Bilirubin treatment significantly downregulated Mrp1 function and expression without affecting integrity of BRB and increased bilirubin levels and phosphorylation of p38 and MK2 in rat retina. In conclusion, BDL downregulates the expression and function of retina Mrp1 by activating the p38 MAPK pathway due to increased bilirubin levels.

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Section: Introductionmentioning

confidence: 99%

Bile Duct Ligation Impairs Function and Expression of Mrp1 at Rat Blood–Retinal Barrier via Bilirubin-Induced P38 MAPK Pathway Activations

Yang

Lin

et al. 2022

IJMS

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“…The results showed that BDL significantly increased the levels of gabapentin in the cortex, hippocampus, and striatum of rats without affecting plasma concentration of gabapentin (Figure 1A); as a result, the brain-to-plasma concentration ratio of gabapentin was significantly upregulated by BDL (Figure 1B). Our previous report showed that BDL has little effect on the integrity of the BBB [36], suggesting that the increased distribution of gabapentin in the brain of BDL rats is attributed to the enhanced function of LAT1. rats (Figure 1E,F).…”

Section: Bdl Increases the Function And Expression Of Lat1 In Brain Tissues Of Ratsmentioning

confidence: 95%

“…BDL rats were developed according to the method previously described in [36]. Shamoperated (sham) rats received the same experimental procedure without bile duct ligation.…”

Section: Development Of Bdl Ratsmentioning

confidence: 99%

Bile Duct Ligation Upregulates Expression and Function of L-Amino Acid Transporter 1 at Blood–Brain Barrier of Rats via Activation of Aryl Hydrocarbon Receptor by Bilirubin

et al. 2021

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Liver failure is associated with increased levels of brain aromatic amino acids (AAAs), whose transport across the blood–brain barrier (BBB) is mainly mediated by L-amino acid transporter 1 (LAT1). We aimed to investigate whether liver failure induced by bile duct ligation (BDL) increases levels of brain AAAs by affecting the expression and function of LAT1. The LAT1 function was assessed using the brain distribution of gabapentin. It was found that BDL significantly increased levels of gabapentin, phenylalanine, and tryptophan in the cortex, hippocampus, and striatum of rats, and upregulated the expression of total LAT1 protein in hippocampus and striatum as well as cortex membrane LAT1 protein. HCMEC/D3 served as in vitro BBB model, and the data showed that both the serum of BDL rats and bilirubin induced LAT1 expression and function, while bilirubin oxidase almost abolished the upregulation of LAT1 protein by bilirubin and the serum of BDL rats. The enhanced function and expression of LAT1 were also observed in the hippocampus and striatum of hyperbilirubinemia rats. Both aryl hydrocarbon receptor (AhR) antagonist α-naphthoflavone and AhR silencing obviously attenuated the upregulation of LAT1 protein by bilirubin or omeprazole. This study provides the first evidence that BDL upregulates LAT1 at the rat BBB, attributed to the activation of AhR by the increased plasma bilirubin. The results highlight the mechanisms causing BDL-increased levels of brain AAAs and their physiological significance.

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“…Cell Culture and Viability Assay hCMEC/D3 cell, an immortalized human cerebral microvascular endothelial cell, is widely utilized as an in vitro BBB model (Qosa et al, 2014;Sánchez-Dengra et al, 2021). It was purchased from FuHeng Cell Center (Shanghai, China) and cultured in RPMI-1640 medium (Invitrogen, Carlsbad, CA, United States) supplemented with 10% fetal bovine serum (FBS) (Invitrogen, Carlsbad, CA, United States) under 5% CO 2 in an incubator (37 °C) as previously described (Qin et al, 2020). For cell viability assay, hCMEC/D3 cells were seeded into 24-well plates at a density of 1×10 5 cells per well.…”

Section: Preparations Of Hepaticmentioning

confidence: 99%

Hepatic Ischemia-Reperfusion Impairs Blood-Brain Barrier Partly Due to Release of Arginase From Injured Liver

Zhu

Zhou

et al. 2021

Front. Pharmacol.

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Aim: Hepatic ischemia-reperfusion (HIR) induces remote organs injury, including the brain. The homeostasis of the brain is maintained by the blood-brain barrier (BBB); thus, we aimed to investigate whether HIR impaired BBB and attempted to elucidate its underlying mechanism.Methods: Cell viability of human cerebral microvascular endothelial cells (hCMEC/D3) was measured following 24 h incubation with a serum of HIR rat undergoing 1 h ischemia and 4 h reperfusion, liver homogenate, or lysate of primary hepatocytes of the rat. The liver homogenate was precipitated using (NH4)2SO4 followed by separation on three columns and electrophoresis to identify the toxic molecule. Cell activity, apoptosis, proliferation, cell cycle, and expressions of proteins related to cell cycle were measured in hCMEC/D3 cells incubated with identified toxic molecules. HIR rats undergoing 1 h ischemia and 24 h reperfusion were developed to determine the release of an identified toxic molecule. BBB function was indexed as permeability to fluorescein and brain water. Endothelial cell proliferation and expressions of proteins related to the cell cycle in cerebral microvessels were measured by immunofluorescence and western blot.Results: Toxic molecule to BBB in the liver was identified to be arginase. Arginase inhibitor nor-NOHA efficiently attenuated hCMEC/D3 damage caused by liver homogenate and serum of HIR rats. Both arginase and serum of HIR rats significantly lowered arginine (Arg) in the culture medium. Arg addition efficiently attenuated the impairment of hCMEC/D3 caused by arginase or Arg deficiency, demonstrating that arginase impaired hCMEC/D3 via depriving Arg. Both arginase and Arg deficiency damaged hCMEC/D3 cells by inhibiting cell proliferation, retarding the cell cycle to G1 phase, and downregulating expressions of cyclin A, cyclin D, CDK2, and CDK4. HIR notably increased plasma arginase activity and lowered Arg level, increased the BBB permeability accompanied with enhanced brain water, and decreased the proliferative cells (marked by Ki67) in cerebral microvessels (marked by CD31) and protein expressions of cyclin A, cyclin D, CDK2 and CDK4 in isolated brain microvessels. Oral supplement of Arg remarkably attenuated these HIR-induced alterations.Conclusion: HIR leads to substantial release of arginase from the injured liver and then deprives systemic Arg. The Arg deficiency further impairs BBB via inhibiting the proliferation of brain microvascular endothelial cells by cell cycle arrest.

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Bile duct ligation enhances AZT CNS toxicity partly by impairing the expression and function of BCRP in rat brain

Cited by 10 publications

References 42 publications

Bile Duct Ligation Impairs Function and Expression of Mrp1 at Rat Blood–Retinal Barrier via Bilirubin-Induced P38 MAPK Pathway Activations

Bile Duct Ligation Impairs Function and Expression of Mrp1 at Rat Blood–Retinal Barrier via Bilirubin-Induced P38 MAPK Pathway Activations

Bile Duct Ligation Upregulates Expression and Function of L-Amino Acid Transporter 1 at Blood–Brain Barrier of Rats via Activation of Aryl Hydrocarbon Receptor by Bilirubin

Hepatic Ischemia-Reperfusion Impairs Blood-Brain Barrier Partly Due to Release of Arginase From Injured Liver

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