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The Mechanism of the Down-Regulation of Hepatic Transporters in Rats with Indomethacin-Induced Intestinal Injury

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Abstract

Background

Previously, we reported that hepatic transporters were down-regulated consistent with intestinal injury in indomethacin (IDM)-treated rats.

Aim

The purpose of this study was to characterize this mechanism of the down-regulation of hepatic transporters in IDM-treated rats.

Methods

Hepatic nuclear receptor expressions, oxidative stress condition and the expression of hepatic transporters were evaluated in rats with IDM-induced intestinal injury with or without the administration of mucosal protectant ornoprostil, a prostaglandin E1 analogue, or aminoguanidine (AG), an iNOS inhibitor.

Results

All the nuclear receptors examined in the present study, which regulates hepatic transporters, were decreased by the administration of IDM. Hepatic glutathione, an indicator of oxidative stress, was significantly reduced compared with control. We then determined the expression of hepatic transporters by semi-quantitative real-time RT-PCR and Western blot analysis in IDM-treated rats with or without the administration of ornoprostil or AG. Ornoprostil recovered the gene expression of Oatp1a1, Oatp1b2 and Mrp2 and protein expression of Mrp2 while it had no effect on Oatp1a1 and Oatp1b2 proteins. These results indicated that the gene expression of hepatic transporters was down-regulated in association with the intestinal injury. On the other hand, there is no effect of AG on the reduced gene expression of hepatic Oatp1a1, Oatp1b2 and Mrp2. In protein expression, AG slightly recovered Mrp2 expression accompanied by a partial decrease in portal NO levels.

Conclusions

We suggest that the transcriptional process influenced by a dysfunction of hepatic nuclear receptors as well as the effect of NO on the post-transcriptional process due to intestinal injury are partially involved in the down-regulation of hepatic transporters.

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Acknowledgments

This work was supported in part by a Grant-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology of Japan, and by a Sasagawa Scientific Research Grant from the Japan Science Society. We are grateful to Drs. Yoshinori Nagata, Hiroyuki Kusuhara, and Yuichi Sugiyama of the University of Tokyo for kindly providing us with rat Oatp1b2 antibody.

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Author notes

  1. Nobuhiro Fujiyama

    Present address: Department of Pharmacy, Akita University Hospital, Akita, Japan

Authors and Affiliations

  1. Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Chiba University, 1-8-1, Inohana, Chūō-ku, Chiba, 260-8675, Japan

    Nobuhiro Fujiyama, Yoshihisa Shitara & Toshiharu Horie

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  1. Nobuhiro Fujiyama
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  2. Yoshihisa Shitara
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  3. Toshiharu Horie
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Correspondence to Toshiharu Horie.

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Fujiyama, N., Shitara, Y. & Horie, T. The Mechanism of the Down-Regulation of Hepatic Transporters in Rats with Indomethacin-Induced Intestinal Injury. Dig Dis Sci 58, 1891–1898 (2013). https://doi.org/10.1007/s10620-013-2587-z

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  • DOI: https://doi.org/10.1007/s10620-013-2587-z

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