Selective Centrilobular Expression of the Aryl Hydrocarbon Receptor in Rat Liver1
- Department of Alcohol Research, National Public Health Institute, Helsinki, Finland and 1Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden (I.J., M.I.-S.)
Abstract
The aryl hydrocarbon receptor (AHR) is a transcriptional activator of genes encoding a group of drug-metabolizing enzymes, including cytochrome P450 1A1 (CYP1A1), glutathioneS-transferase, tumor-associated aldehyde dehydrogenase and quinone reductase. Both the constitutive and inducible expression of these genes in the liver is zonated, i.e., dominant in hepatocytes of the centrilobular region, a poorly understood position-dependent phenomenon. By comparing cell lysates obtained from opposite acinar regions we observed that immunoreactive AHR protein was 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 zonation. By contrast, only slight zonation of the AHR nuclear translocator mRNA was observed. Treatment of rats with omeprazole, an atypical nonligand activator of the AHR, caused a zone-specific induction of CYP1A1 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.
Footnotes
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Send reprint requests to: Dr. Kai O. Lindros, National Public Health Institute, Department of Alcohol Research, Box 719, 00101 Helsinki, Finland.
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↵1 This work was supported in part by grants from The Swedish Medical Research Council and from Astra Hässle AB, Sweden.
- Abbreviations:
- AH
- aryl hydrocarbon
- AHR
- aryl hydrocarbon receptor
- RT-PCR
- reverse transcriptase polymerase chain reaction
- ARNT
- aryl hydrocarbon receptor nuclear translocator
- 3MC
- 3-methylcholanthrene
- βNF
- β-naphthoflavone
- TCDD
- 2,3,7,8-tetrachlorodibenzo-p-dioxin
- PBS
- phosphate-buffered saline
- pv
- perivenous
- pp
- periportal
- bp
- basepair
- XRE
- xenobiotic responsive element
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- Received December 27, 1995.
- Accepted September 13, 1996.
- The American Society for Pharmacology and Experimental Therapeutics
