Alteration of P-gp Expression after Intestinal Ischemia-reperfusion Following 16-h Fasting in Rats

Ogura, Jiro; Fujikawa, Asuka; Maruyama, Haruhiko; Kobayashi, Masaki; Itagaki, Shirou; Iseki, Ken

doi:10.1248/yakushi.131.453

Cited by 7 publications

(5 citation statements)

References 39 publications

(36 reference statements)

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“…These results suggested that IL-6 is one of main causes of the decrease in MRP2, FXR, PXR and CAR expression levels. We previously reported the alteration of malondialdehyde (MDA) level, which is a marker of organ injury after I/R, in the liver (28). The increase in MDA level was associated with the increase in IL-6 and with the decrease in MRP2, FXR, PXR and CAR expression levels, suggesting that the decrease in FXR, PXR and CAR expression levels, at least in part, might be caused the liver injury after intestinal I/R.…”

Section: Discussionmentioning

confidence: 99%

The Decrease in Farnesoid X Receptor, Pregnane X Receptor and Constitutive Androstane Receptor in the Liver after Intestinal Ischemia-Reperfusion

Ogura¹,

Terada²,

Tsujimoto³

et al. 2012

J Pharm Pharm Sci

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Purpose. Intestinal ischemia-reperfusion (I/R) damages remote organs, including the liver, and promotes multi-organ failure (MOF). However, the molecular mechanisms underlying acute liver injury after intestinal I/R have not been completely elucidated. Farnesoid X receptor (FXR), pregnane X receptor (PXR) and constitutive androstane receptor (CAR) regulate metabolizing enzymes and transporters, and coordinately prevent hepatotoxicity reflecting an inability of appropriate excretion of endogenous toxic compounds. In this study, we assessed FXR, PXR and CAR expression levels and their localization levels in nuclei in the liver after intestinal I/R. We also investigated the effect of IL-6 on FXR, PXR and CAR expression levels and their localization levels in nuclei in in vitro experiments. Methods. We used intestinal I/R model rats. Moreover, HepG2 cells were used in in vitro study. Real-time PCR and Western blotting were used to assess mRNA and protein expression levels. Nuclear receptor localization in nuclei was analyzed by Western blotting using nuclear extracts. Results. FXR and PXR expression levels began to be decreased at 3 h, and FXR, PXR and CAR expression levels were decreased at 6 h after intestinal I/R. The localization levels of FXR, PXR and CAR in nuclei began to be decreased at 3 h, and all of them were decreased at 6 h after intestinal I/R. In HepG2 cells, FXR, PXR and CAR expression levels were decreased by 0.5-1 ng/mL, 0.5-100 ng/mL and 100 ng/mL IL-6 treatment for 24 h, respectively. FXR, PXR and CAR localization levels in nuclei were suppressed by 0.5-10 ng/mL, 10-100 ng/mL and 10-100 ng/mL IL-6 treatment for 24 h, respectively. Conclusions. FXR, PXR and CAR expression levels are decreased in the liver after intestinal I/R. IL-6 is one of main causes the decreases in expressions of these receptors. This article is open to POST-PUBLICATION REVIEW. Registered readers (see “For Readers”) may comment by clicking on ABSTRACT on the issue’s contents page.

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Section: Discussionmentioning

confidence: 99%

The Decrease in Farnesoid X Receptor, Pregnane X Receptor and Constitutive Androstane Receptor in the Liver after Intestinal Ischemia-Reperfusion

Ogura¹,

Terada²,

Tsujimoto³

et al. 2012

J Pharm Pharm Sci

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“…The extent of ROS-induced oxidative damage was assessed indirectly by measuring the level of malondialdehyde (MDA), an intermediate product of lipid peroxidation, as described previously (15). For this study, a PBS suspension of Caco-2 cells and tissue homogenate were used.…”

Section: Oxidative Injury Assessmentmentioning

confidence: 99%

Intestinal P-glycoprotein Expression is Multimodally Regulated by Intestinal Ischemia-Reperfusion

et al. 2014

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Purpose. Reactive oxygen species (ROS) have multiple physiological effects that are amount-dependent. ROS are one of the causes of intestinal ischemia-reperfusion (I/R) injury. In this study, we investigated whether the amount of ROS and the degree of intestinal I/R injury affect the expression level of P-glycoprotein (P-gp). Methods. We used hydrogen peroxide (H2O2) as ROS in in vitro experiments. Intestinal I/R model rats, which were subjected 15-min ischemia (I/R-15), were used in in vivo experiments. Results. P-gp expression in Caco-2 cells was increased in response to 1 µM of H2O2 but decreased upon exposure to 10 mM of H2O2. We previously reported that P-gp expression is decreased after intestinal I/R with 30-min ischemia (I/R-30), which time a large amount of ROS is generated. I/R-15 induced slightly less mucosal and oxidative injury than did I/R-30. P-gp expression in the jejunum was increased at 1 h after I/R-15, and ileal paracellular permeability was increased. The blood concentration of tacrolimus, a P-gp substrate, was lower during 0-20 min but was higher during 40-90 min post-administration compared with that in the sham-operated rats. P-gp expression in the ileum was decreased at 6 h after I/R-15, due to abnormal localization of P-gp, resulting in a high blood tacrolimus concentration in rats reperfused for 6 h. Conclusions. ROS multimodally regulate P-gp expression depending on its amount. This is important for understanding the pattern of P-gp expression after intestinal I/R. This article is open to POST-PUBLICATION REVIEW. Registered readers (see “For Readers”) may comment by clicking on ABSTRACT on the issue’s contents page.

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“…Evaluation of oxidative stress through determination of malondialdehyde (MDA) levels was performed as described previously (Ogura et al, 2011). Thiobarbituric acid (TBA) solution consisted of 2.6 mM TBA, 918 mM trichloroacetic acid, 0.3 mM HCl and 1.8 mM 2, 6-di-tert-butyl-4-metylphenol in 22% ethanol.…”

Section: Evaluation Of Oxidative Stressmentioning

confidence: 99%

Effect of oxidative stress on expression and function of human and rat organic anion transporting polypeptides in the liver

Tsujimoto¹,

Ogura²,

Kuwayama³

et al. 2013

International Journal of Pharmaceutics

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Alteration of P-gp Expression after Intestinal Ischemia-reperfusion Following 16-h Fasting in Rats

Cited by 7 publications

References 39 publications

The Decrease in Farnesoid X Receptor, Pregnane X Receptor and Constitutive Androstane Receptor in the Liver after Intestinal Ischemia-Reperfusion

The Decrease in Farnesoid X Receptor, Pregnane X Receptor and Constitutive Androstane Receptor in the Liver after Intestinal Ischemia-Reperfusion

Intestinal P-glycoprotein Expression is Multimodally Regulated by Intestinal Ischemia-Reperfusion

Effect of oxidative stress on expression and function of human and rat organic anion transporting polypeptides in the liver

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