Induction of Detoxifying Enzymes in Rodent White Adipose Tissue by Aryl Hydrocarbon Receptor Agonists and Antioxidants

Abstract

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 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.

Oxidised LDL up‐regulate CD36 expression by the Nrf2 pathway in 3T3‐L1 preadipocytes

“…In the nucleus Nrf2 binds to antioxidant response elements (ARE) present in the promoter of genes encoding antioxidant/detoxifying enzymes. It has been hypothesized that Nrf2 represents a common way for activating cell defences in tissues, as rat adipose tissue [25], by regulating also cell-specific target genes [33].…”

Identification of a Cytochrome P4502E1/Bid/C1q-dependent Axis Mediating Inflammation in Adipose Tissue after Chronic Ethanol Feeding to Mice

“…In the liver, ethanol-induced oxidant stress is due at least in part to ethanol metabolism via CYP2E1 (12). Although white adipose tissue has negligible alcohol dehydrogenase activity (34), CYP2E1 mRNA and protein are expressed in adipose tissue (35) and can be induced by chronic ethanol exposure (4). Here we also show that chronic ethanol feeding increases CYP2E1 activity in adipose tissue (Fig.…”

Changes in the Expression of Cytochromes P450 and Nuclear Receptors in the Liver of Genetically Diabetic db/db Mice

“…13,14) Portions of the microsomes (5 mg) and the nuclear extract (50 mg) were separated by SDS-polyacrylamide gel (9%, 12%, respectively) electrophoresis and transferred onto a polyvinylidene fluoride membrane (Immobilon-P; Millipore, Billerica, MA, U.S.A.). The membrane was incubated with primary antibodies and appropriate horseradish peroxidaselabeled secondary antibodies, and signals were detected with Lumi GLO reagent (Cell Signaling Technology, Beverly, MA, U.S.A.).…”

“…Reverse Transcription-Polymerase Chain Reaction Total RNAs were prepared by the acid guanidine-phenolchloroform method using TRIzol reagent (Invitrogen, Carlsbad, CA, U.S.A.), and quantitative reverse transcriptionpolymerase chain reaction (RT-PCR) experiments were carried out as described previously 14) using SYBR Premix Ex Taq (Takara Bio) with 7500 Real Time PCR System (Applied Biosystems, Foster City, CA, U.S.A.).…”