Inverse acinar regulation of Mrp2 and 3 represents an adaptive response to hepatocellular cholestatic injury. We studied whether obstructive cholestasis (BDL) and LPS treatment affect the zonal expression of Bsep (Abcb11), Mrp4 (Abcc4), Ntcp (Slc10a1) and Oatp isoforms (Slco1a1, Slco1a4 and slco1b2) in rat liver, as analyzed by semiquantitative immunofluorescence. Contribution of TNF- and IL-1 to transporter zonation in obstructive cholestasis was studied by cytokine inactivation. In normal liver Bsep, Mrp4, Ntcp and Oatp1a1 were homogeneously distributed in the acinus, whereas Oatp1a4 and Oatp1b2 expression increased from zone 1 to 3. Glutamine synthetase-positive pericentral hepatocytes exhibited markedly lower Oatp1a4 expression than the remaining zone 3 hepatocytes. In cholestatic liver Bsep and Ntcp immunofluorescence in periportal hepatocytes significantly decreased to 66+4% (p<0.01) and 67+7% (p<0.05), whereas it was not altered in pericentral hepatocytes. Oatp1a4 was significantly induced in hepatocytes with a primarily low expression, i.e. in periportal hepatocytes and in glutamine synthetase-positive pericentral hepatocytes. Likewise, Oatp1b2 was upregulated in periportal hepatocytes. Mrp4 zonal induction was homogeneous. Inactivation of TNF- and IL-1 prevented periportal down-regulation of Bsep. Recruitment of neutrophiles and polymorphonuclear cells mainly occurred in the periportal zone. Likewise, IL-1 induction was largely found periportally. No significant transporter zonation was seen following LPS treatment. In conclusion, zonal down-regulation of Bsep in obstructive cholestasis is associated with portal inflammation and is mediated by TNF- and IL-1. Periportal down-regulation Ntcp and induction of Oatp1a4 und Oatp1b2 may represent adaptive mechanisms to reduce cholestatic injury in hepatocytes with profound down-regulation of Bsep and Mrp2.