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, β-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 WATs (epididymal, perirenal, and mesenteric) to a greater degree 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.
Footnotes
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This work was supported in part by a Grant-in-Aid for Encouragement of Young Scientists and The 21st Century Center of Excellence Program from the Ministry of Education, Culture, Sports, Science and Technology.
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Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.
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doi:10.1124/dmd.105.007286.
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ABBREVIATIONS: P450, cytochrome P450; AhR, aryl hydrocarbon receptor; TCDD, 2,3,7,8-tetrachlorodibenzo-p-dioxin; Hsp90, 90-kDa heat shock protein; Arnt, AhR nuclear translocator; XRE, xenobiotic response element; NQO1, NAD(P)H:quinone oxidoreductase; GST, glutathione S-transferase; UGT, UDP-glucronosyltransferase; Nrf2, NF-E2-related factor 2; BHQ, tert-butylhydroquinone; ARE, antioxidant responsive element; BNF, β-naphthoflavone; WAT, white adipose tissue; ALDH, aldehyde dehydrogenase; DCPIP, 2,6-dichlorphenoleindophenole; CDNB, 1-chloro-2,4-dinitrobenzene; 3MC, 3-methylcholanthrene; RPS9, ribosomal protein S9; SV, stromal-vascular; RT-PCR, reverse transcription-polymerase chain reaction; BAT, brown adipose tissue; UCP1, uncoupling protein 1; HO-1, heme oxygenase-1; Ct, threshold cycle number.
- Received September 13, 2005.
- Accepted March 27, 2006.
- The American Society for Pharmacology and Experimental Therapeutics
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