Received for publication July 25, 2006.
Revised September 19, 2006.
Accepted for publication September 19, 2006.

Endogenous Hepatic Expression of the Hepatitis B Virus X-associated Protein 2 is Adequate for Maximal Association with Aryl Hydrocarbon Receptor-HSP90 Complexes

Abstract

The aryl hydrocarbon receptor (AHR) is a ligand activated transcription factor that acts as an environmental sensor by binding to a wide variety of xenobiotics. AHR activation serves to combat xenotoxic stress by inducing metabolic enzyme expression in the liver. The hepatitis B virus X-associated protein (XAP2) is a component of the cytosolic AHR complex and modulates AHR transcriptional properties in vitro and in cell culture and yeast systems. Expression of XAP2 is low in liver compared to other non-hepatic tissues and the AHR exhibits high ligand-induced transcriptional activity. Since XAP2 has been demonstrated to repress AHR activity, we hypothesized that XAP2 may be limiting in liver and that increasing XAP2 levels would attenuate AHR transcriptional activity. To this end transgenic mice were generated that exhibit hepatocyte-specific elevation in XAP2 expression. Transgenic XAP2 expression was restricted to liver, and its ability to complex with the AHR was verified. Gene expression experiments were performed by inducing AHR transcriptional activity with -napthoflavone via intraperitoneal injection, and mRNA quantification was done by real-time PCR. Wild type and transgenic animals showed no difference in constitutive or ligand-induced CYP1A1, CYP1A2, UGT1A2, NQO1, CAR, or NRF2 mRNA expression. Sucrose density fractionation and AHR immunoprecipitation experiments found little or no stoichiometric increase in bound XAP2 to the AHR between genotypes. Gene array studies were performed to identify novel XAP2-regulated targets. Taken together, this work shows that despite the relatively low level of XAP2 in liver, it is not a limiting component in AHR regulation.

Key words: PPARs, Cytochrome P450, Phase II enzymes, Quinone oxidoreductase, UDP-glucuronyltransferases, Ah receptor

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