REGULATION OF<i>CYP1A1</i>GENE EXPRESSION BY THE ANTIOXIDANT<i>TERT-</i>BUTYLHYDROQUINONE

Schreiber, Thomas D.; Köhle, Christoph; Buckler, Felicitas; Schmohl, Stefan; Braeuning, Albert; Schmiechen, Alexander; Schwarz, Michael; Münzel, Peter A.

doi:10.1124/dmd.106.009662

Cited by 22 publications

(25 citation statements)

References 32 publications

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“…Some phase II enzymes are reported to be induced by tBHQ via the AhR pathway (Schreiber et al, 2006). To test the induction potential of tBHQ in rat intestine, we incubated slices (small intestine and colon) with tBHQ (50 M) for 0, 5, and 24 h, after which slices were incubated for 3 h with 7HC.…”

Section: Resultsmentioning

confidence: 99%

“…The AhR pathway is known to be involved in the induction of both phase I ( (Schreiber et al, 2006) has been reported to induce UGT activity in Caco-2 cells (Munzel et al, 1999), and, indeed, it induced glucuronidation in small intestine but not in colon slices. However, two other AhR ligands, 3MC and bNF, did not induce 7HC conjugation via UGT1A6 (Ikushiro et al, 2004) or UGT1A7/8 (Webb et al, 2005), which is in line with reported findings that UGT1A6 -8 mRNA expression was not induced in rat duodenum after in vivo administration of bNF (Shelby and Klaassen, 2006).…”

Section: Discussionmentioning

confidence: 99%

“…We chose bNF (Lin and Lu, 1998), 3-methylcholanthrene (3MC) (Abdelrahim et al, 2006), indirubin (IR) (Guengerich et al, 2004), and tert-butylhydroquinone (tBHQ) (Schreiber et al, 2006) as AhR ligands. Dexamethasone (DEX) was used as a GR/PXR ligand (Pascussi et al, 2001) and phenobarbital (PB) as a CAR mediator (Wang and LeCluyse, 2003).…”

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Induction of Phase I and II Drug Metabolism in Rat Small Intestine and Colon in Vitro

et al. 2007

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ABSTRACT:The aim of this study was to evaluate drug metabolism in rat small intestinal and colon precision-cut slices during 24 h of incubation and the applicability of these slices for enzyme induction studies. Various parameters were evaluated: intracellular levels of ATP (general viability marker), alkaline phosphatase activity (specific epithelial marker), villin expression (specific epithelial marker), and metabolic rates of 7-ethoxycoumarin (CYP1A), testosterone (CYP3A and CYP2B), and 7-hydroxycoumarin (glucuronide and sulfate conjugation) conversions. ATP and villin remained constant up to, respectively, 5 and 8 h in small intestine and up to 24 h in colon. The metabolic rate remained constant in small intestinal slices up to 8 h and decreased afterward to 24 to 92%, depending on the substrate studied. The inducibility of metabolism in small intestinal and colon slices was tested with several inducers at various concentrations and incubation times. The following inducers were used: 3-methylcholanthrene, ␤-naphthoflavone, indirubin, and tertbutylhydroquinone (aryl hydrocarbon receptor ligands), dexamethasone (glucocorticoid receptor/pregnane X receptor ligand) and phenobarbital (constitutive androstane receptor ligand). After incubation with inducers, metabolic rates were evaluated with 7-ethoxycoumarin and testosterone (phase I) and 7-hydroxycoumarin (phase II) as substrate. All inducers elevated the metabolic rates consistent with the available published in vivo induction data. Induction of enzyme activity was already detectable after 5 h (small intestine) and after 8 h (colon) for 3-methylcholanthrene and ␤-naphthoflavone and was clearly detectable for all tested inducers after 24 h (up to 20-fold compared with noninduced controls). In conclusion, small intestinal and colon precision-cut slices are useful for metabolism and enzyme induction studies.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Induction of Phase I and II Drug Metabolism in Rat Small Intestine and Colon in Vitro

et al. 2007

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“…Hepatoma cells were transfected with a firefly luciferase reporter plasmid containing three copies of the DRE3 motif (Kress et al, 1998) from the human CYP1A1 promoter (Schreiber et al, 2006) using Lipofectamine 2000 (Invitrogen, Karlsruhe, Germany). Plasmid pRL-CMV (Promega, Madison, WI) expressing Renilla luciferase under the control of the constitutively active cytomegaly virus promoter was cotransfected.…”

Section: Methodsmentioning

confidence: 99%

The Glycogen Synthase Kinase Inhibitor 3-(2,4-Dichlorophenyl)-4-(1-methyl-1H-indol-3-yl)-1H-pyrrole-2,5-dione (SB216763) Is a Partial Agonist of the Aryl Hydrocarbon Receptor

Braeuning¹,

Buchmann²

2009

Drug Metab Dispos

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ABSTRACT:Kinase inhibitors are frequently used tools in signal transduction research. 3-(2,4-Dichlorophenyl)-4-(1-methyl-1H-indol-3-yl)-1H-pyrrole-2,5-dione (SB216763), a potent inhibitor of glycogen synthase kinase 3␤ (GSK3␤), is frequently used to activate ␤-catenin signaling by mimicking the action of Wnt molecules. ␤-Catenin is a crucial player in the regulation of hepatic drug metabolism. Thus, it is of particular importance to know whether the tools used to study the effects of ␤-catenin signaling may affect the respective drugmetabolizing target enzymes in an unwanted manner. In this study, we show that SB216763 is able to induce cytochrome P450 1a1 (Cyp1a1) expression in a dose-dependent manner in mouse hepatoma cells. Moreover, SB216763 is able to inhibit Cyp1a1 induction by the prototype aryl hydrocarbon receptor (AhR) ligand 2,3,7,8-tetrachloro-p-dibenzodioxin. Cyp1a1 induction by SB216763 is independent of GSK3␤ and the ␤-catenin pathway. Instead, SB216763 induces Cyp1a1 by activation of AhR-mediated transcription. The present results suggest that SB216763 acts as a partial agonist of the AhR.A variety of cellular signal transduction pathways are regulated by phosphorylation/dephosphorylation events, and a huge number of small molecule kinase inhibitors has been developed allowing for the blockade or activation of distinct signaling cascades. Besides the fact that many kinase inhibitors-often acting in an ATP-competitive manner-do not provide satisfactory specificity toward only one single kinase (Davies et al., 2000;Bain et al., 2007), there are also several reports which demonstrate that some of these molecules can act through additional mechanisms that are different from kinase inhibition. An example of this difference is the interaction with nuclear receptors such as the xenobiotic sensor aryl hydrocarbon receptor (AhR), which is a crucial player in the expression of various drug-metabolizing enzymes. In the absence of a ligand, the AhR is complexed by heat shock proteins in the cytosol. Upon binding of a ligand, mostly a planar hydrophobic molecule, the AhR translocates to the nucleus, releases the chaperones, and dimerizes with the Arnt protein. The AhR/Arnt heterodimer then binds to so-called dioxin response elements (DREs) on the DNA and activates transcription of target genes such as cytochrome P450 1a1 (Cyp1a1). For a recent review on AhR-dependent signal transduction, see Beischlag et al. (2008).The widely used kinase inhibitors U0126, PD98059, and SP600125 are ligands and partial agonists of the AhR (Reiners et al., 1998;Joiakim et al., 2003;Andrieux et al., 2004;Dvorak et al., 2008).Several other kinase inhibitors also affect the process of AhR activation by direct interaction with the AhR or by more complex indirect mechanisms, as reviewed in Braeuning (2009). Because most of the kinase inhibitors available from commercial suppliers have never been tested for a possible interplay with xenobiotic sensors, one might overlook such nonkinase-related properties and attribute the observed eff...

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“…Induction of a wide range of antioxidative potentials such as elevation of the glutathione levels and GSTs, via the activation of ARE, was believed to be responsible for the protective effect of tBHQ [8]. Furthermore, Gharavi and El-Kadi [9], and Schreiber et al [10] demonstrated that tBHQ could also induce Phase I XMEs, cytochrome P450 1A1 (CYP1A1) gene expression directly in an aryl hydrocarbon receptor (AHR)-dependent manner in murine and human hepatoma cells. However, only limited information is available about the potential influence of tBHQ on DA metabolism in fish.…”

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confidence: 99%

Effects of dietary tert-butylhydroquinone on domoic acid metabolism and transcription of detoxification-related liver genes in red sea bream Pagrus major

Liang

Shen

et al. 2013

Chin. Sci. Bull.

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Domoic acid (DA) is a neuroexcitatory amino acid that is produced by Pseudo-nitzschia during harmful algal blooms (HAB). Accumulation of DA can be transferred through food chain and cause neuronal damage in marine animal and in human. Like other algal toxins, DA was suggested to increase the oxidative stress and increase the detoxification-related gene expression in fish. The widely used food antioxidant, tert-butylhydroquinone (tBHQ), was known to induce a wide range of antioxidative potentials such as elevation of the glutathione levels and glutathione S-transferases (GSTs), via the activation of antioxidant response elements (AREs). In this study, the influences of dietary tBHQ on domoic acid (DA) metabolism and detoxification-related gene transcription were investigated both in vivo and in vitro. Oral administration of tBHQ resulted in significant decreases of DA accumulation of liver tissues in which red sea bream were fed with a single dose of 10 mg DA and 100 mg tBHQ per kg body weight per fish. Real-time PCR further revealed that the mRNA levels of AHR/ARNT/CYP1A1/GSTA1/GSTR were up-regulated in the above liver tissues at 72 h post tBHQ treatment. In consistence, tBHQ exposure also resulted in increased mRNA transcription of GSTA1, GSTA2 and GSTR in cultured red sea bream hepatocytes. Collectively, our findings in this research suggested that the dietary intake of tBHQ accelerated DA metabolism in fish, through mechanisms involving altered transcription of detoxificationrelated liver genes. Domoic acid is an excitatory neurotoxin produced by marine diatoms of the genus Pseudo-nitzschia. It is responsible for a neurotoxic disease called amnesic shellfish poisoning (ASP) in human and marine mammals following consumption of DA (domoic acid)-contaminated fish. Symptoms of ASP include short-term memory loss, brain damage and death in severe cases. During harmful algal blooms, accumulation of high concentration of DA has been reported for a number of marine species such as types of cockles (Cerastoderma edule), crabs (Cancer magister), furrow shell (Scrobicularia plana), mussels (Mytilus edulis), razor clams (Siliqua patula) and scallops (Pecten maximus) [1][2][3]. Other fish species, such as anchovies and mackerel, have also been shown to accumulate DA, although at much lower levels compared with those found in shellfish [3]. A majority of DA uptake was excreted via kidney and bile in fish, with the remaining absorbed DA mainly detected in liver, heart, spleen and muscle [4]. Limited data was available on in vivo metabolism in fish, although previous studies suggested that the biotransformation and detoxification pathways of Phase I and/or Phase II xenobiotic metabolism enzymes (XMEs) were involved in DA metabolism [5]. Further investigations using intraperitoneal (I.P.) injection of DA in fish revealed that a receptor-mediated induction of

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REGULATION OFCYP1A1GENE EXPRESSION BY THE ANTIOXIDANTTERT-BUTYLHYDROQUINONE

Cited by 22 publications

References 32 publications

Induction of Phase I and II Drug Metabolism in Rat Small Intestine and Colon in Vitro

Induction of Phase I and II Drug Metabolism in Rat Small Intestine and Colon in Vitro

The Glycogen Synthase Kinase Inhibitor 3-(2,4-Dichlorophenyl)-4-(1-methyl-1H-indol-3-yl)-1H-pyrrole-2,5-dione (SB216763) Is a Partial Agonist of the Aryl Hydrocarbon Receptor

Effects of dietary tert-butylhydroquinone on domoic acid metabolism and transcription of detoxification-related liver genes in red sea bream Pagrus major

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