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Differential regulation of basolateral and canalicular transporter expression in rat liver in chronic renal failure
Author(s) -
Holzer B.,
Stieger B.,
Folkers G.,
Meier P. J.,
Fattinger K.
Publication year - 2005
Publication title -
clinical pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.941
H-Index - 188
eISSN - 1532-6535
pISSN - 0009-9236
DOI - 10.1016/j.clpt.2004.12.023
Subject(s) - multidrug resistance associated protein 2 , organic anion transporter 1 , transporter , downregulation and upregulation , creatinine , endocrinology , chemistry , medicine , western blot , pharmacology , kidney , atp binding cassette transporter , biochemistry , gene
Background Renal failure (RF) decreases the hepatic elimination of substrates of basolateral Organic Anion Transporting Polypeptides (Oatp) and canalicular Multidrug Resistance Protein 2 (Mrp2), e.g. bromosulfophthalein, cerivastatin, and pravastatin. Therefore we investigated, the expression of these hepatocellular transporters in RF. Methods Male SD rats (120–140g) underwent 2‐step 5/6‐nephrectomy (6, N) or sham operation (8, C), were pair fed and killed after 6 weeks. Hepatic transporter expression was evaluated in a total liver membrane fraction (TLMF) by semiquantitative Western Blot analysis. Results N and C exhibited similar body weights, liver weights and transaminases. N had uremia, i. e. 314% increased serum creatinine, 698% increased serum urea and 73% decreased creatinine clearance as compared to C (100%). TLMF showed similar recovery and enrichment of canalicular marker enzyme activities in N and C. In N liver, transporter expression showed the following changes as compared to C (100%): Ntcp +20±13%, Oatp1a1 −61±6%, Oatp1a4 −43±13%, Oatp1b2 −72±10%, Mrp2 +25±41%, Mdr1 +7±18%, Mdr2 +96±34%. Thus chronic RF decreases the expression of basolateral Oatps in rat liver, whereas expression of canalicular transporters remains stable or increases. Conclusion Downregulation of hepatic basolateral Oatps might explain the decreased hepatic drug elimination, while upregulation of some canalicular transporters may compensate for reduced renal drug elimination in chronic RF. Clinical Pharmacology & Therapeutics (2005) 77 , P34–P34; doi: 10.1016/j.clpt.2004.12.023