INDUCTION OF DETOXIFYING ENZYMES IN RODENT WHITE ADIPOSE TISSUE BY ARYL HYDROCARBON RECEPTOR AGONISTS AND ANTIOXIDANTS Export

@article{citeulike:783432, 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, {beta}-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. 10.1124/dmd.105.007286}, address = {Department of Pharmaco-Biochemistry, School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka-ken 422-8526, Japan.}, author = {Yoshinari, Kouichi and Okino, Nao and Sato, Takeshi and Sugatani, Junko and Miwa, Masao}, citeulike-article-id = {783432}, citeulike-linkout-0 = {http://dx.doi.org/10.1124/dmd.105.007286}, citeulike-linkout-1 = {http://dmd.aspetjournals.org/cgi/content/abstract/34/7/1081}, citeulike-linkout-2 = {http://view.ncbi.nlm.nih.gov/pubmed/16581946}, citeulike-linkout-3 = {http://www.hubmed.org/display.cgi?uids=16581946}, day = {1}, doi = {10.1124/dmd.105.007286}, issn = {0090-9556}, journal = {Drug Metab Dispos}, keywords = {adipose\_tisue, ahr, antioxidants, bioaccumulation, nrf2, wat}, month = {July}, number = {7}, pages = {1081--1089}, posted-at = {2009-02-13 13:51:41}, priority = {3}, title = {INDUCTION OF DETOXIFYING ENZYMES IN RODENT WHITE ADIPOSE TISSUE BY ARYL HYDROCARBON RECEPTOR AGONISTS AND ANTIOXIDANTS}, url = {http://dx.doi.org/10.1124/dmd.105.007286}, volume = {34}, year = {2006} }

TY - JOUR ID - citeulike:783432 L3 - citeulike-article-id:783432 N2 - 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, {beta}-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. 10.1124/dmd.105.007286 IS - 7 JF - Drug Metab Dispos SN - 0090-9556 AD - Department of Pharmaco-Biochemistry, School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka-ken 422-8526, Japan. EP - 1089 TI - INDUCTION OF DETOXIFYING ENZYMES IN RODENT WHITE ADIPOSE TISSUE BY ARYL HYDROCARBON RECEPTOR AGONISTS AND ANTIOXIDANTS VL - 34 SP - 1081 KW - adipose_tisue KW - ahr KW - antioxidants KW - bioaccumulation KW - nrf2 KW - wat AU - Yoshinari, Kouichi AU - Okino, Nao AU - Sato, Takeshi AU - Sugatani, Junko AU - Miwa, Masao PY - 2006/07/01/ UR - http://dx.doi.org/10.1124/dmd.105.007286 ER -