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Cited by 362

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Up–Regulation of the Multidrug Resistance Genes, Mrp1 And Mdr1b , and Down–Regulation of the Organic Anion Transporter, Mrp2, and the Bile Salt Transporter, Spgp, in Endotoxemic Rat Liver

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Vos, Thera A., Hooiveld, Guido J., Koning, Hans, Childs, Sarah, Meijer, Dirk K., Moshage, Han, Jansen, Peter L., Müller, Michael·1998·Hepatology
DOI 10.1002/hep.510280625
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Abstract

Endotoxin–induced cholestasis is mainly caused by an impaired canalicular secretion. Mrp2, the canalicular multispecific organic anion transporter, is strongly down–regulated in this situation, and canalicular bile salt secretion is also reduced. We hypothesized that other adenosine triphosphate-binding cassette (ABC) transporters may compensate for the decreased transport activity to protect the cell from cytokine–induced oxidative damage. Therefore, we examined the expression of ABC–transport proteins in membrane fractions of whole liver and of isolated hepatocytes of endotoxin–treated rats and performed reverse–transcriptase polymerase chain reaction (RT–PCR) on mRNA isolated from these livers. In addition, the localization of these transporters was examined using confocal scanning laser microscopy. By 6 hours after endotoxin administration, we found a clear increase of mrp1 mRNA and protein, whereas mrp2 mRNA and protein were decreased. This was confirmed in isolated hepatocytes. In addition,mdr1b mRNA was strongly increased, whereas mdr1a and mdr2 mRNA did not change significantly. Both the mRNA and protein levels of the sister of P–glycoprotein (spgp), the recently cloned bile salt transporter, decreased. After endotoxin treatment, the normally sharply delineated canalicular staining of mrp2 and spgp had changed to a fuzzy pattern, suggesting localization in a subapical compartment. We conclude that endotoxin–induced cholestasis is caused by decreased mrp2 and spgp levels, as well as an abnormal localization of these proteins. The simultaneous up–regulation of mrp1 and mdr1b may confer resistance to hepatocytes against cytokine–induced metabolic stress.

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Metadata

Authors
Vos, T. A., Hooiveld, G. J., Koning, H., Childs, S., Meijer, D. K., Moshage, H., Jansen, P. L., & Müller, M.
Venue
Hepatology
Publisher
Ovid Technologies (Wolters Kluwer Health)
Published
1998-12
Volume
28
Issue
6
Pages
1637-1644
ISSN
0270-9139 (ISSN-L)
DOI
10.1002/hep.510280625
OpenAlex
W2160486989
Cited by
362
References
0
FWCI
10.83
Type
journal article
Language
en
Open access
bronze
Licence
doi.wiley.com/10.1002/tdm_license_1.1 (tdm, 6118 d)

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CoChat. (2026). Citation check: Up–Regulation of the Multidrug Resistance Genes, Mrp1 And Mdr1b , and Down–Regulation of the Organic Anion Transporter, Mrp2, and the Bile Salt Transporter, Spgp, in Endotoxemic Rat Liver. https://app.cochat.ai/papers/10.1002/hep.510280625
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Vos, T. A., Hooiveld, G. J., Koning, H., Childs, S., Meijer, D. K., Moshage, H., Jansen, P. L., & Müller, M. (1998). Up–Regulation of the Multidrug Resistance Genes, Mrp1 And Mdr1b , and Down–Regulation of the Organic Anion Transporter, Mrp2, and the Bile Salt Transporter, Spgp, in Endotoxemic Rat Liver. Hepatology. https://doi.org/10.1002/hep.510280625

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