Received for publication September 15, 2005.
Revised March 12, 2006.
Accepted for publication March 27, 2006.

Induction of detoxifying enzymes in rodent white adipose tissue by aryl hydrocarbon receptor agonists and antioxidants

Abstract

The liver is the main organ of drug metabolism, but the expression and induction by xenobiotics of drug-metabolizing enzymes is also often observed in extrahepatic tissues. Recently, we reported that lipophilic cytochrome P450 inducers, -naphthoflavone (BNF), phenobarbital and dexamethasone, induced CYP1, CYP2B and CYP3A enzymes, respectively, in rat epididymal white adipose tissue (WAT) at both mRNA and protein levels. To further confirm the xenobiotic-induced expression of drug-metabolizing enzymes in adipose tissue, we studied the induction of CYP1A1 and other detoxifying enzymes by aryl hydrocarbon receptor (AhR) agonists and antioxidants. BNF increased CYP1A1 mRNA levels in several visceral WAT (epididymal, perirenal and mesenteric) greater than in subcutaneous WAT in rats. Using C57BL/6 and DBA/2 mice with different responsiveness to aryl hydrocarbons and detecting cytoplasmic levels of AhR proteins, we have demonstrated that AhR mediates this CYP1A1 induction by BNF in WAT. Moreover, the NF-E2-related factor 2 (Nrf2)/antioxidant responsive element pathway is also functional in WAT, since BNF, which is known to activate both AhR and Nrf2, and antioxidants including tert-butylhydroquinone, 1-chloro-2,4-dinitrobenzene and menadione, induced the expression of Nrf2-target genes (NAD(P)H:quinone oxidoreductase, glutathione S-transferase A subunits and heme oxygenase-1) in rats and mice. These results suggest that both AhR and Nrf2 pathways are active in WAT and that lipophilic compounds accumulated in WAT can activate these transcription factors to increase detoxification capability in the tissue.

Key words: Ah receptor, antioxidants, cytochrome P450, enzyme induction, extrahepatic cytochrome P450, extrahepatic drug metabolism, toxicology