Impaired function and expression of P-glycoprotein in blood–brain barrier of streptozotocin-induced diabetic rats

Liu, Haiyan; Xu, Xiao; Zhihong, Yang; Deng, Yejun; Liu, Xiaodong; Xie, Lin

doi:10.1016/j.brainres.2006.09.061

Cited by 72 publications

(53 citation statements)

References 26 publications

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“…We also used the cocultured rat brain microvessel endothelial cell monolayers with 100% diabetic rat serum as in vitro diabetic model to examine the effect of the diabetes on the function of Pglycoprotein (15) and breastcancer resistance protein (27) in the blood-brain barrier. Here, HepG2 cells were cocultured with 100% diabetic serum as in vitro diabetic model to investigate effects of serum from diabetic rats on hepatic CYP3A4 activity.…”

Section: Discussionmentioning

confidence: 99%

“…HepG2 cells were exposed to serum from diabetic rats, serving as an in vitro diabetic model to mimic the diabetic situation (15). Subconfluent (approximately 80%) HepG2 cells seeded in 24well plates were incu bated in presence of 100% serum from diabetic or control rats for 48 h. The CYP3A4 activity was measured as described above.…”

Section: Effect Of Diabetic Rat Serum On Cyp3a4 Activity In Hepg2 Cellsmentioning

confidence: 99%

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Increased Levels of Fatty Acids Contributed to Induction of Hepatic CYP3A4 Activity Induced by Diabetes — In Vitro Evidence From HepG2 Cell and Fa2N-4 Cell Lines

Duan

et al. 2014

J Pharmacol Sci

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Abstract.Accumulating evidences have shown that diabetes upregulated the function and expression of CYP3A4, but the mechanism remained unclear. In this study, HepG2 cells were incubated with serum from diabetic rats induced by streptozotocin, and the activity of CYP3A4 was measured by substrate metabolism. Results showed that incubation with diabetic serum significantly induced CYP3A4 activity in HepG2 cells. To identify the specific factors contribut ing to the regulation, the abnormally altered components in diabetic serum, including glucose, insulin, cholesterol, and free fatty acids were screened. It was found that only fatty acids concen trationdependently upregulated CYP3A4 activity, and the induction by fatty acids was further confirmed in Fa2N4 cells. Data from western blotting and QTPCR showed that induction of CYP3A4 activity was associated with upregulation of CYP3A4 protein and mRNA levels. In addition, effects of pharmacological inhibitors on fatty acid-induced CYP3A4 activity were studied. The results indicated that the induction of CYP3A4 activity by oleic acid may be partly via AMPK, PKC, and NFkB-dependent pathways, whereas that by palmitic acid was possibly associated with the PKCdependent pathway. In conclusion, the increased levels of fatty acids may be one of the reasons leading to the elevated function and expression of CYP3A4 under diabetic conditions.

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Section: Discussionmentioning

confidence: 99%

Section: Effect Of Diabetic Rat Serum On Cyp3a4 Activity In Hepg2 Cellsmentioning

confidence: 99%

Increased Levels of Fatty Acids Contributed to Induction of Hepatic CYP3A4 Activity Induced by Diabetes — In Vitro Evidence From HepG2 Cell and Fa2N-4 Cell Lines

Duan

et al. 2014

J Pharmacol Sci

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“…Biochemical parameters in STZ-induced diabetic rats STZ-induced diabetes is a well-documented model of experimental T1DM [15] . As expected, a single administration of STZ to rats produced diabetic symptoms, including polyphagia, polyuria, polydipsia and a loss of body weight.…”

Section: Resultsmentioning

confidence: 99%

Tissue cholesterol content alterations in streptozotocin-induced diabetic rats

Wang

Liu

et al. 2012

Acta Pharmacol Sin

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Aim: Diabetes is associated with elevated serum total cholesterol level and disrupted lipoprotein subfractions. The aim of this study was to examine alterations in the tissue cholesterol contents closely related to diabetic complications. Methods: Intraperitoneal injection of streptozotocin was used to induce type 1 diabetes in adult male Sprague-Dawley rats. On d 35 after the injection, liver, heart, intestine, kidney, pancreas, cerebral cortex and hippocampus were isolated from the rats. The content of total and free cholesterol in the tissues was determined using HPLC. The ATP-binding cassette protein A1 (ABCA1) protein and ApoE mRNA were measured using Western blot and QT-PCR analyses, respectively. Results: In diabetic rats, the level of free cholesterol was significantly decreased in the peripheral tissues, but significantly elevated in hippocampus, as compared with those in the control rats. Diabetic rats showed a trend of decreasing the total cholesterol level in the peripheral tissues, but significant change was only found in kidney and liver. In diabetic rats, the level of the ABCA1 protein was significantly increased in the peripheral tissues and cerebral cortex; the expression of ApoE mRNA was slightly decreased in hippocampus and cerebral cortex, but the change had no statistical significance. Conclusion: Type 1 diabetes decreases the free cholesterol content in the peripheral tissues and increases the free cholesterol content in hippocampus. The decreased free cholesterol level in the peripheral tissues may be partly due to the increased expression of the ABCA1 protein.

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“…The concentrations of prazosin in the cerebral cortex, hippocampus and plasma were determined using high-performance liquid chromatography (HPLC). The BBB integrity of Sham and BDL rats was investigated by the extravasation of Evans Blue in the brains of Sham and BDL rats, according to a previously described method [8] . Briefly, Evans Blue (2% in saline, 4 mL/kg) was injected intravenously into the rats in groups II and III and in the Sham group.…”

Section: Animalsmentioning

confidence: 99%

“…The efficacy and toxicity of drugs targeting the central nervous system are largely deter-mined by the function and expression of these transporters and by their selectivity and affinity toward the substrates [6,7] . Several studies have verified that the functions of P-gp and Mrp2 at BBB are affected by various disease states, including diabetes mellitus [8,9] , acute myeloid leukemia [10] , cancer [11] and liver failure [12][13][14] . Our previous studies have also demonstrated that both the function and expression of P-gp and Mrp2 are markedly altered in brain tissues in thioacetamide/ hyperammonemia-induced liver dysfunction rodent models [15,16] .…”

Section: Introductionmentioning

confidence: 99%

Unconjugated bilirubin elevation impairs the function and expression of breast cancer resistance protein (BCRP) at the blood-brain barrier in bile duct-ligated rats

Ling

Zhang

et al. 2016

Acta Pharmacol Sin

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Aim: Liver failure is associated with dyshomeostasis of efflux transporters at the blood-brain barrier (BBB), which contributes to hepatic encephalopathy. In this study we examined whether breast cancer resistance protein (BCRP), a major efflux transporter at the BBB, was altered during liver failure in rats. Methods: Rats underwent bile duct ligation (BDL) surgery, and then were sacrificed after intravenous injection of prazosin on d3, d7 and d14. The brains and blood samples were collected. BCRP function at the BBB was assessed by the brain-to-plasma prazosin concentration ratio; Evans Blue extravasation in the brain tissues was used as an indicator of BBB integrity. The protein levels of BCRP in the brain tissues were detected. Human cerebral microvessel endothelial cells (HCMEC/D3) and Madin-Darby canine kidney cells expressing human BCRP (MDCK-BCRP) were tested in vitro. In addition, hyperbilirubinemia (HB) was induced in rats by intravenous injection of unconjugated bilirubin (UCB). Results: BDL rats exhibited progressive decline of liver function and HB from d3 to d14. In the brain tissues of BDL rats, both the function and protein levels of BCRP were progressively decreased, whereas the BBB integrity was intact. Furthermore, BDL rat serum significantly decreased BCRP function and protein levels in HCMEC/D3 cells. Among the abnormally altered components in BDL rat serum tested, UCB (10, 25 µmol/L) dose-dependently inhibit BCRP function and protein levels in HCMEC/D3 cells, whereas 3 bile acids (CDCA, UDCA and DCA) had no effect. Similar results were obtained in MDCK-BCRP cells and in the brains of HB rats. Correlation analysis revealed that UCB levels were negatively correlated with BCRP expression in the brain tissues of BDL rats and HB rats as well as in two types of cells tested in vitro. Conclusion: UCB elevation in BDL rats impairs the function and expression of BCRP at the BBB, thus contributing to hepatic encephalopathy.

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Impaired function and expression of P-glycoprotein in blood–brain barrier of streptozotocin-induced diabetic rats

Cited by 72 publications

References 26 publications

Increased Levels of Fatty Acids Contributed to Induction of Hepatic CYP3A4 Activity Induced by Diabetes — In Vitro Evidence From HepG2 Cell and Fa2N-4 Cell Lines

Increased Levels of Fatty Acids Contributed to Induction of Hepatic CYP3A4 Activity Induced by Diabetes — In Vitro Evidence From HepG2 Cell and Fa2N-4 Cell Lines

Tissue cholesterol content alterations in streptozotocin-induced diabetic rats

Unconjugated bilirubin elevation impairs the function and expression of breast cancer resistance protein (BCRP) at the blood-brain barrier in bile duct-ligated rats

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