Alteration of Mrp2 and P-gp expression, including expression in remote organs, after intestinal ischemia-reperfusion

Ogura, Jiro; Kobayashi, Masaki; Itagaki, Shirou; Hirano, Takeshi; Iseki, Ken

doi:10.1016/j.lfs.2008.04.019

Cited by 20 publications

(43 citation statements)

References 34 publications

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“…It has been also known that intestinal I/R induces the release of inflammatory cytokines, and these are known to decrease Oatps expression. We previously reported that serum concentration of IL-6 significantly increased at 3 to 6 h in our intestinal I/R model rats (11,26). Because Oatp1a1 and Oatp2b1 expressions were decreased at 1 h after intestinal I/R, IL-6 might not cause the decrease in Oatps expressions after intestinal I/R.…”

Section: Discussionmentioning

confidence: 72%

“…Thus, the low biliary excretion of BSP in intestinal I/R rats reperfused for 6 h ( Fig. 4B and Table 3) might be caused by the decrease in Mrp2 expression (11). When Mrp2 function is suppressed, Mrp3 excretes Mrp2 substrates from hepatocytes to blood circulation.…”

Section: Discussionmentioning

confidence: 96%

“…Intestinal I/R model Surgical procedures were carried out as described in previous reports (10,11,16). The animals were anesthetized with sodium pentobarbital (30 mg/kg body weight, i.p.…”

Section: Animalsmentioning

confidence: 99%

“…It is known that expression levels of ABC transporters are altered by intestinal I/R (9)(10)(11)(12)(13)(14). These alterations occur in the intestine, liver and kidney.…”

Section: Introductionmentioning

confidence: 99%

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Intestinal Ischemia-Reperfusion Suppresses Biliary Excretion of Hepatic Organic Anion Transporting Polypeptides Substrate

Maruyama¹,

Ogura²,

Fujikawa³

et al. 2013

J Pharm Pharm Sci

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-Purpose. Intestinal ischemia-reperfusion (I/R) causes gut dysfunction and promotes multi-organ failure. The liver and kidney can be affected by multi-organ failure after intestinal I/R. Organic anion transporting polypeptides (OATPs) and organic anion transporters (OATs) are recognized in a broad spectrum from endogenous compounds to xenobiotics, including clinically important drugs. Therefore, it is important for understanding the pharmacokinetics to obtain evidence of alterations in OATPs and OATs expression and transport activities. In the present study, we investigated the expression of rat Oatps and Oats after intestinal I/R. Methods. We used intestinal ischemia-reperfusion (I/R) model rats. Real-time PCR and Western blotting were used to assess mRNA and protein expression levels. Plasma concentration and biliary excretion of sulfobromophthalein (BSP), which is used as a model compound of organic anion drugs, were measured after intravenous administration in intestinal I/R rats. Results. Although Oat1 and Oat3 mRNA levels were not altered in the kidney, Oatp1a1, Oatp1b2 and Oatp2b1 mRNA levels in the liver were significantly decreased at 1-6 h after intestinal I/R. Moreover, Oatp1a1 and Oatp2b1 protein expression levels were decreased at 1 h after intestinal I/R. Plasma concentration of BSP, which is a typical substrate of Oatps, in intestinal I/R rats reperfused 1 h was increased than that in sham-operated rats. Moreover, the area under the concentration-time curve (AUC0-90) in intestinal I/R rats reperfused 1 h was significantly increased than that in sham-operated rats. The total clearance (CLtot) and the biliary clearance (CLbile) in intestinal I/R rats reperfused 1 h were significantly decreased than those in sham-operated rats. Conclusions. Oatp1a1 and Oatp2b1 expression levels are decreased by intestinal I/R. The decreases in these transporters cause alteration of pharmacokinetics of organic anion compound. The newly found influence of intestinal I/R on the expression and function of Oatps may be a key to perform appropriate drug therapy.

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Section: Discussionmentioning

confidence: 72%

Section: Discussionmentioning

confidence: 96%

“…Intestinal I/R model Surgical procedures were carried out as described in previous reports (10,11,16). The animals were anesthetized with sodium pentobarbital (30 mg/kg body weight, i.p.…”

Section: Animalsmentioning

confidence: 99%

“…It is known that expression levels of ABC transporters are altered by intestinal I/R (9)(10)(11)(12)(13)(14). These alterations occur in the intestine, liver and kidney.…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Intestinal Ischemia-Reperfusion Suppresses Biliary Excretion of Hepatic Organic Anion Transporting Polypeptides Substrate

Maruyama¹,

Ogura²,

Fujikawa³

et al. 2013

J Pharm Pharm Sci

Self Cite

View full text Add to dashboard Cite

show abstract

“…Intestinal I/R model Surgical procedures were carried out as described in a previous report (17). The animals were anesthetized with sodium pentobarbital (30 mg/kg body weight, i.p.…”

Section: Animalsmentioning

confidence: 99%

Intestinal Ischemia-Reperfusion Increases Efflux for Uric Acid Via Paracellular Route in the Intestine, but Decreases that Via Transcellular Route Mediated by BCRP

Ogura¹,

Kuwayama²,

Takaya³

et al. 2012

J Pharm Pharm Sci

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-Purpose. Uric acid is thought to be one of the most important antioxidants in human biological fluids. Intestinal ischemia-reperfusion (I/R) is an important factor associated with high rates of morbidity and mortality. Reactive oxygen species (ROS) are responsible for intestinal I/R injury. The aim of this study was to clarify the efflux for uric acid from the intestine after intestinal I/R. Methods. We used intestinal ischemia-reperfusion (I/R) model rats. Serosal to mucosal flux for [14 C]-uric acid was assessed by using Ussing-type diffusion chambers. BCRP/Bcrp expression was assessed by Western blot analysis. Caco-2 cells were used for a model of the intestinal epithelium, and rotenone was used as a mitochondrial dysfunction inducer. Results. Serosal to mucosal flux for uric acid was increased after intestinal I/R, and that for mannitol was also increased. Ko143, which is a BCRP inhibitor, did not affect the uric acid transport. The decreasing uric acid transport mediated by Bcrp was caused by decrease in the level of Bcrp homodimer, bridged by an S-S bond. The suppression of Bcrp S-S bond formation was associated with mitochondrial dysfunction. Moreover, BCRP S-S bond formation activity was decreased by rotenone in Caco-2 cells. Conclusions. Serosal to mucosal flux for uric acid is significantly increased via the paracelluler route, but that via the transcellular route mediated by Bcrp is decreased after intestinal I/R. The decreasing uric acid flux mediated by Bcrp is caused by suppression of Bcrp S-S bond formation. This suppression of Bcrp S-S bond formation may be related to mitochondrial dysfunction.

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Association between α‐defensin 5 and the expression and function of P‐glycoprotein in differentiated intestinal Caco‐2 cells

Yasuda

Kubota

Okamoto

et al. 2023

Biopharm & Drug Disp

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Abstractα‐Defensin 5 is known to be secreted by Paneth cells in the small intestine and plays an important role in eliminating pathogenic microorganisms. It has been reported that a decrease in α‐defensin 5 level in the human small intestine is a risk of inflammatory bowel disease (IBD). Furthermore, P‐glycoprotein (P‐gp), a member of the ATP‐binding cassette transporter superfamily, encoded by the ABCB1/MDR1 gene, plays an important role in the front line of host defense by protecting the gastrointestinal barrier from xenobiotic accumulation and may contribute to the development and persistence of IBD. Therefore, we examined the relationship between α‐defensin 5 and the expression and function of P‐gp using a human gastrointestinal model cell line (Caco‐2). We found that MDR1 mRNA and P‐gp protein level were increased in Caco‐2 cells as well as α‐defensin 5 secretion corresponded with the duration of cell culture. Exposure to α‐defensin 5 peptide and recombinant tumor necrosis factor‐α (TNF‐α) significantly increased the expression and function P‐gp. The mRNA levels of interleukin (IL)‐8, IL‐6, TNF‐α, IL‐1β, and IL‐2 were also increased following exposure to TNF‐α, similar to α‐defensin 5 treatment. These results suggest that α‐defensin 5 regulates P‐gp expression and function by increasing TNF‐α expression in Caco‐2 cells.

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Alteration of Mrp2 and P-gp expression, including expression in remote organs, after intestinal ischemia-reperfusion

Cited by 20 publications

References 34 publications

Intestinal Ischemia-Reperfusion Suppresses Biliary Excretion of Hepatic Organic Anion Transporting Polypeptides Substrate

Intestinal Ischemia-Reperfusion Suppresses Biliary Excretion of Hepatic Organic Anion Transporting Polypeptides Substrate

Intestinal Ischemia-Reperfusion Increases Efflux for Uric Acid Via Paracellular Route in the Intestine, but Decreases that Via Transcellular Route Mediated by BCRP

Association between α‐defensin 5 and the expression and function of P‐glycoprotein in differentiated intestinal Caco‐2 cells

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