SELECTIVE CENTRILOBULAR EXPRESSION OF THE ARYL-HYDROCARBON RECEPTOR IN RAT-LIVER

The aryl hydrocarbon receptor (AHR) is a transcriptional activator of genes encoding a group of drug-metabolizing enzymes, including cytochr ome P450 1A1 (CYP1A1), glutathione S-transferase, tumor-associated ald ehyde dehydrogenase and quinone reductase. Both the constitutive and i nducible expression of these genes in the liver is zonated, i.e., domi nant in hepatocytes of the centrilobular region, a poorly understood p osition-dependent phenomenon. By comparing cell lysates obtained from opposite acinar regions we observed that immunoreactive AHR protein wa s almost exclusively confined to centrilobular cells. The AHR mRNA, as analyzed from cell lysates by reverse transcriptase polymerase chain reaction, exhibited a similar, although somewhat less pronounced zonat ion. By contrast, only slight zonation of the AHR nuclear translocator mRNA was observed. Treatment of rats with omeprazole, an atypical non ligand activator of the AHR, caused a zone-specific induction of CYP1A 1 in the centrilobular region similar to that seen after pretreatment with the AHR ligand 3-methylcholanthrene. Our results suggest that the zone-restricted expression of AHR protein will allow the constitutive and inducible expression of AHR-regulated genes in the centrilobular region, but will limit their expression in the periportal region.