Alternative transporter pathways in patients with untreated early‐stage and late‐stage primary biliary cirrhosis

Takeyama, Yoshifumi; Uehara, Yuko; Inomata, Shinjiro; Morihara, Daisuke; Nishizawa, Shinya; Ueda, Seinosuke; Matsumoto, Teruo; Tanaka, Takashi; Anan, Akira; Nishimura, H; Irie, Makoto; Iwata, Kazuo; Shakado, Satoshi; Sohda, Tetsuro; Sakisaka, Shotaro

doi:10.1111/j.1478-3231.2008.01846.x

Cited by 15 publications

(13 citation statements)

References 38 publications

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“…191 MRP1 and OST α/β, which are not expressed or expressed at low levels in normal hepatocytes, are upregulated in patients with PBC. 149,190,193,194 Consistent with the literature findings, data from our laboratory indicated that MRP1 protein was expressed in liver tissue from a patient with PBC (Figure 1). Interestingly, our findings suggest that MRP1 was expressed primarily in the inflamed tissues in macrophages around the hepatocytes in PBC.…”

Section: Introductionsupporting

confidence: 89%

“…189 Interestingly, it was reported that these alterations may be related to the adaptation of transporters, and that expression patterns may change from early to late stage PBC. 190,193 In addition to the changes in expression, the localization of MRP2 was altered in PBC stage III. 191 MRP1 and OST α/β, which are not expressed or expressed at low levels in normal hepatocytes, are upregulated in patients with PBC.…”

Section: Introductionmentioning

confidence: 99%

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Effect of Liver Disease on Hepatic Transporter Expression and Function

Thakkar

Slizgi

Brouwer

2017

Journal of Pharmaceutical Sciences

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Liver disease can alter the disposition of xenobiotics and endogenous substances. Regulatory agencies such as the Food and Drug Administration (FDA) and the European Medicines Evaluation Agency (EMEA) recommend, if possible, studying the effect of liver disease on drugs under development to guide specific dose recommendations in these patients. While extensive research has been conducted to characterize the effect of liver disease on drug-metabolizing enzymes, emerging data have implicated that the expression and/or function of hepatobiliary transport proteins also are altered in liver disease. This review summarizes recent developments in the field, which may have implications for understanding altered disposition, safety, and of efficacy of new and existing drugs. A brief review of liver physiology and hepatic transporter localization/function is provided. Then, the expression and function of hepatic transporters in cholestasis, hepatitis C infection, hepatocellular carcinoma (HCC), human immunodeficiency virus (HIV) infection, non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH), and primary biliary cirrhosis (PBC) are reviewed. In the absence of clinical data, nonclinical information in animal models is presented. This review aims to advance the understanding of altered expression and function of hepatic transporters in liver disease and the implications of such changes on drug disposition.

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Section: Introductionsupporting

confidence: 89%

Section: Introductionmentioning

confidence: 99%

Effect of Liver Disease on Hepatic Transporter Expression and Function

Thakkar

Slizgi

Brouwer

2017

Journal of Pharmaceutical Sciences

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“…Therefore, cirrhotic liver parenchyma may have reduced enhancement in the hepatobiliary phase relative to non‐cirrhotic parenchyma due to an impaired uptake and transport mechanism for Gd‐EOB‐DTPA. We have previously described the expression of MRP2 and the downregulation of hepatic MRP2 mRNA levels in LC‐PBC …”

Section: Discussionmentioning

confidence: 99%

“…In response, hepatobiliary transporters are expressed to prevent bile acid accumulation in hepatocytes . We previously described that the lack of adaptation to the upregulation of hepatobiliary transporters may be related to PBC progression …”

Section: Introductionmentioning

confidence: 99%

“…Gd‐EOB‐DTPA is transported into hepatocytes via OATP1B3 and is excreted into bile canaliculi via the multidrug resistance‐associated protein 2 (MRP2) . We have previously described that hepatic MRP2 mRNA levels are downregulated in PBC liver cirrhosis (LC) patients . Gd‐EOB‐DTPA is taken up by hepatocytes and undergoes hepatobiliary excretion.…”

Section: Introductionmentioning

confidence: 99%

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Gadolinium‐ethoxybenzyl‐diethylenetriamine pentaacetic acid‐enhanced magnetic resonance imaging as a useful detection method for advanced primary biliary cirrhosis

Takeyama

Tsuchiya

Kunimoto

et al. 2015

Hepatology Research

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Aim:In primary biliary cirrhosis (PBC), damaged hepatocytes resulting from chronic cholestasis follow a compensatory mechanism that alters hepatobiliary transporter expression to reduce the accumulation of potentially toxic compounds such as bile acid. Organic anion transporter peptide 1B3 (OATP1B3), which transports agents such as gadolinium-ethoxybenzyldiethylenetriamine pentaacetic acid (Gd-EOB-DTPA), has reduced expression in the late stages of PBC. Therefore, we investigated the use of Gd-EOB-DTPA-enhanced magnetic resonance imaging (MRI) as a useful detection method for the advanced staging of PBC. Methods: Stage IÀIII PBC (non-liver cirrhosis [LC]-PBC, n = 12),stage IV (LC-PBC, n = 6), and nonÀPBC patients (control group, n = 4) were included in this study. We obtained liver tissue samples by percutaneous liver biopsy. Hepatic OATP1B3 expression was determined immunohistochemically, and OATP1B3 mRNA levels were assessed using real-time reverse transcription polymerase chain reaction. The relative enhancement (RE) in the hepatobiliary phase was calculated using the signal intensity of Gd-EOB-DTPA-enhanced MRI.Results: Immunohistochemistry revealed markedly reduced expression of OATP1B3 in hepatocytes around the central vein in LC-PBC patients. Hepatic OATP1B3 mRNA expression in LC-PBC patients was significantly lower than that in non-LC-PBC patients (P < 0.05). The RE on MRI was significantly decreased in the LC-PBC group (0.33 ± 0.14) compared with the non-LC-PBC (0.91 ± 0.15, P < 0.01) and control (0.92 ± 0.20, P < 0.01) groups.Conclusion: Gd-EOB-DTPA-enhanced MRI may provide a useful detection method for liver disease in patients with LC-PBC.

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Adaptive Regulation of Hepatocyte Transporters in Cholestasis

Boyer

2009

The Liver

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Alternative transporter pathways in patients with untreated early‐stage and late‐stage primary biliary cirrhosis

Cited by 15 publications

References 38 publications

Effect of Liver Disease on Hepatic Transporter Expression and Function

Effect of Liver Disease on Hepatic Transporter Expression and Function

Gadolinium‐ethoxybenzyl‐diethylenetriamine pentaacetic acid‐enhanced magnetic resonance imaging as a useful detection method for advanced primary biliary cirrhosis

Adaptive Regulation of Hepatocyte Transporters in Cholestasis

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