Functional Induction of P-glycoprotein in the Blood-Brain Barrier of Streptozotocin-Induced Diabetic Rats: Evidence for the Involvement of Nuclear Factor-κB, a Nitrosative Stress-Sensitive Transcription Factor, in the Regulation

Maeng, Han‐Joo; Kim, Mi-Hwa; Jin, H. N.; Shin, Sook; Tsuruo, T.; Kim, Sang Geon; Kim, Dae‐Duk; Shim, Chang‐Koo; Chung, Suk‐Jae

doi:10.1124/dmd.107.015800

Cited by 52 publications

(54 citation statements)

References 37 publications

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“…Induction of Mdr1 and Cyp3a has been observed in tissues from male rats with STZ-induced diabetes (Maeng et al, 2007;Kameyama et al, 2008;Hasegawa et al, 2010), but reports in female rats with STZ-induced diabetes or STZ-induced GDM are limited (Mulay and Varma, 1984;Anger et al, 2009;Anger and Piquette-Miller, 2010). We posit that disruptions to lipid and glucose homeostasis underlie the alterations to drug transporter and Cyp3a2 expression that were observed in STZ-induced GDM.…”

Section: Discussionmentioning

confidence: 90%

Mechanisms of Reduced Maternal and Fetal Lopinavir Exposure in a Rat Model of Gestational Diabetes

Anger

Piquette-Miller²

2011

Drug Metab Dispos

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ABSTRACT:Lopinavir (LPV) is the preferred HIV protease inhibitor in pregnancy, but it is unknown if gestational diabetes mellitus (GDM) affects its disposition. Hepatic protein expression and plasma protein binding are altered in rodent models of GDM. Because LPV is influenced by hepatic transporters and metabolic enzymes and is highly protein bound, it was hypothesized that streptozotocininduced GDM would alter its disposition. Maternal and fetal tissues were collected from GDM rats and controls 45 min after LPV injection. In another cohort, fetuses were serially extracted 5 to 60 min after injection. LPV was quantified using liquid chromatography tandem mass spectrometry. Expression of relevant transporters, such as Multidrug resistance protein 1 (Mdr1), and cytochrome P450 3a2 (Cyp3a2), which metabolizes LPV in rodents, was measured in maternal liver via quantitative reverse transcriptase polymerase chain reaction and Western blot analysis. Expression of relevant transporters also was measured in placenta via quantitative reverse transcriptase polymerase chain reaction. Protein binding was determined by ultrafiltration. Relative to controls, we observed dramatically reduced maternal and fetal LPV exposure in GDM. Compared with controls, maternal hepatic Mdr1 and Cyp3a2 were up-regulated, and protein binding was reduced in the GDM group. Increased Mdr1-and Cyp3a2-mediated hepatobiliary clearance, coupled with a larger unbound LPV fraction, is likely to have facilitated hepatic elimination, thereby decreasing maternal and fetal exposure. Not surprisingly, up-regulation of Mdr1 and Cyp3a2's transcriptional regulator, pregnane X receptor, was demonstrated in maternal liver via Western blot analysis. Up-regulation of Mdr1 in placentas isolated from the GDM group likely also contributed to decreased fetal exposure to LPV. This study provides preclinical support for an as yet unreported drug-disease (LPV-GDM) interaction.

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Section: Discussionmentioning

confidence: 90%

Mechanisms of Reduced Maternal and Fetal Lopinavir Exposure in a Rat Model of Gestational Diabetes

Anger

Piquette-Miller²

2011

Drug Metab Dispos

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“…Caco-2 cells co-treated with SNP and pharmacological inhibitors The free radical scavengers ascorbate (antioxidant [8] , 2 mmol/L), PTIO (NO scavenger [17] , 2 mmol/L), GSH (active against nitrosative stress [17] , 2 mmol/L) and uric acid (peroxynitrite scavenger [19] , 2 mmol/L) as well as several signal pathway inhibitors: chelerythrine (a PKC inhibitor, 5 µmol/L), wortmannin (a PI3K/Akt inhibitor, 1 µmol/L), SB203580 (a p38 MAPK inhibitor, 10 µmol/L) and ODQ (a specific guanylate cyclase inhibitor, 50 µmol/L) [20,21] were used to investigate whether these inhibitors reverse the alteration in P-gp function induced by SNP. Caco-2 cells were pretreated with a pharmacological inhibitor for 1 h, then either SNP or normal medium was added and incubated for 4 and 24 h, respectively [22] .…”

Section: Caco-2 Cells Treated With No Donorsmentioning

confidence: 99%

“…Previous reports have indicated that the expression and function of P-gp are dysregulated under pathophysiological situations such as diabetes mellitus [4,5] , chronic renal failure [6] and inflammation [7] . It is becoming increasingly clear that nitric oxide and its related nitrogen species (NOx) [8] are crucial regulatory mediators of the function and expression of P-gp and other transporters under pathophysiological conditions [8][9][10][11][12][13][14] . NO-mediated nitrosative stress was reported to stimulate the function and expression of P-gp in the blood-brain barrier of streptozotocin-treated diabetic rats [8] .…”

mentioning

confidence: 99%

“…It is becoming increasingly clear that nitric oxide and its related nitrogen species (NOx) [8] are crucial regulatory mediators of the function and expression of P-gp and other transporters under pathophysiological conditions [8][9][10][11][12][13][14] . NO-mediated nitrosative stress was reported to stimulate the function and expression of P-gp in the blood-brain barrier of streptozotocin-treated diabetic rats [8] . Activation of inductible nitric oxide synthase (iNOS) seemed to explain the increase in the expression and function of intestinal P-gp in interferon-γ-induced human intestinal cells, as evidenced by the fact that coadministration of the iNOS inhibitor L-N 6 -(1-iminoethyl)-lysin abrogated the cytokine-mediated increase in P-gp expression and function [9] .…”

mentioning

confidence: 99%

“…In addition, Caco-2 cells express high levels of P-gp and have been widely used for the study of P-gp function and intestinal absorption [16] . Three different types of NO donors, SNP, SIN-1, and SNAP [8,17] were used as source of NO. The function of P-gp was assessed using uptake of Rhodamine123 (Rho123) by Caco-2 cells.…”

mentioning

confidence: 99%

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Biphasic regulation of P-glycoprotein function and expression by NO donors in Caco-2 cells

Duan

Liu

et al. 2012

Acta Pharmacol Sin

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Aim: To investigate the effects of nitric oxide (NO) donors on the function and expression of P-glycoprotein (P-gp) in Caco-2 cells. Methods: Caco-2 cells were exposed to NO donors for designated times. P-gp function and expression were assessed using Rhodamine123 uptake assay and Western blotting, respectively. Intracellular reactive oxygen species (iROS) and intracellular reactive nitrogen species (iRNS) levels were measured using ROS and RNS assay kits, respectively. Results: Exposure of Caco-2 cells to 0.1 or 2 mmol/L of sodium nitroprusside (SNP) affected the function and expression of P-gp in concentration-and time-dependent manners. A short-term (4 h) exposure reduced P-gp function and expression accompanied with significantly increased levels of iROS and iRNS. In contrast, a long-term (24 h) exposure stimulated the P-gp function and expression. The stimulatory effects of 2 mmol/L SNP was less profound as compared to those caused by 0.1 mmol/L SNP. The other NO donors SIN-1 and SNAP showed similar effects. Neither the NO scavenger PTIO (2 mmol/L) nor soluble guanylate cyclase inhibitor ODQ (50 µmol/L) reversed the SNP-induced alteration of P-gp function. On the other hand, free radical scavengers ascorbate, glutathione and uric acid (2 mmol/L for each), PKC inhibitor chelerythrine (5 µmol/L), PI3K/Akt inhibitor wortmannin (1 µmol/L) and p38 MAPK inhibitor SB203580 (10 µmol/L) reversed the upregulation of P-gp function by the long-term exposure to SNP, but these agents had no effect on the impaired P-gp function following the short-term exposure to SNP. Conclusion: NO donors time-dependently regulate P-gp function and expression in Caco-2 cells: short-term exposure impairs P-gp function and expression, whereas long-term exposure stimulates P-gp function and expression. The regulation occurs via a NO-independent mechanism.

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Comparative pharmacokinetic study of paclitaxel and docetaxel in streptozotocin‐induced diabetic rats

Lee

et al. 2012

Biopharm & Drug Disp

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The pharmacokinetics of paclitaxel and docetaxel were compared in diabetic rats induced by streptozotocin (DMIS rats) and the impact of altered expression of cytochrome P450 3A (Cyp3A) and P-glycoprotein (P-gp) in the diabetic state. The pharmacokinetics of paclitaxel and docetaxel were determined after intravenous (5 mg/kg) and oral (30 and 40 mg/kg, respectively) administration to both groups and the mRNA expression levels of Cyp3A isozymes and Mdr1a and Mdr1b in the liver and small intestine were determined in control and DMIS rats. After intravenous administration, the AUC and clearance of paclitaxel and docetaxel were not significantly different in DMIS vs control rats. After oral administration, the AUC and C(max) of paclitaxel in DMIS rats were significantly greater than those in the control rats, whereas those of docetaxel was not changed significantly. The mRNA expression levels of hepatic Cyp3A1, Cyp3A9 and Mdr1b were significantly increased in DMIS compared with the control rats. In the intestine, Cyp3A62 expression decreased in the DMIS rats compared with the controls. Thus the pharmacokinetic changes of taxanes observed in the DMIS rats were attributed to changes in P-gp and Cyp3A, predominant factors that control the absorption of paclitaxel and docetaxel, respectively. It seemed that there were different susceptibilities to intestinal P-gp and Cyp3A between the two taxanes.

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Functional Induction of P-glycoprotein in the Blood-Brain Barrier of Streptozotocin-Induced Diabetic Rats: Evidence for the Involvement of Nuclear Factor-κB, a Nitrosative Stress-Sensitive Transcription Factor, in the Regulation

Cited by 52 publications

References 37 publications

Mechanisms of Reduced Maternal and Fetal Lopinavir Exposure in a Rat Model of Gestational Diabetes

Mechanisms of Reduced Maternal and Fetal Lopinavir Exposure in a Rat Model of Gestational Diabetes

Biphasic regulation of P-glycoprotein function and expression by NO donors in Caco-2 cells

Comparative pharmacokinetic study of paclitaxel and docetaxel in streptozotocin‐induced diabetic rats

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