Hepatobiliary organic anion transporters are differentially regulated in acute toxic liver injury induced by carbon tetrachloride

Background/Aims: Hepatobiliary transporters are down-regulated in cholestasis, but their expression in acute, noncholestatic, cytokine-mediated liver injury is unknown. Thus we studied the molecular mechanisms, by which sodium taurocholate cotransporting polypeptide (Ntep), organic anion transporting polypeptide 1 (Oatp1), Oatp2, Oatp4, multidrug-resistance protein 2 (Mrp2) and bile salt export pump (Bsep) are regulated in liver injury induced by carbon tetrachloride (CCl4). Methods: mRNA and protein levels were determined in rats 24 and 72 h after CCl4 injection. Transporter gene transcription and binding activities of Ntcp and Mrp2 transactivators were assessed by nuclear runoff and electrophoretic mobility shift assays. Results: mRNA levels significantly declined to 41 +/- 44% for Ntep, 65 +/- 41 % for Oatp1 and 64 +/- 28% for Oatp2, but remained unchanged for Oatp4, canalicular Mrp2 and Bsep. Protein levels declined only for Oatp4 (-50 +/- 17%) and Ntcp (-23 +/- 13%) at 24 h. Reduced mRNA levels (Ntcp, Oatp1, Oatp2) were associated with decreased transcriptional activities. Binding activity of Ntcp transactivators (hepatocyte nuclear factor 1 alpha (HNF1alpha) and CAAT enhancer binding protein alpha (C/EBPalpha) were reduced by 24 h, whereas retinoid X receptor alpha (RXRalpha):retinoid acid receptor alpha (RARalpha) as transactivator of both Ntcp and Mrp2 remained unaltered. Recovery of acute hepatitis and changes in gene expression occurred after 72 h. Conclusions: Acute liver injury results hi down-regulation of basolateral organic anion transporters similar to liver regeneration after partial hepatectomy, but in contrast to endotoxin-induced cholestasis. Maintained binding activity of RXRalpha:RARalpha may explain differences in Mrp2 expression. (C) 2002 European Association for the Study of the Liver. Published by Elsevier Science B.V. All rights reserved.