Nuclear Receptor-Mediated Transcriptional Regulation in Phase I, II, and III Xenobiotic Metabolizing Systems

Nakata, Kotoko; Tanaka, Yoshitomo; Nakano, Tatsuya; Adachi, Tatsuhiko; Tanaka, Hiroshi; Kaminuma, Tsuguchika; Ishikawa, Toshihisa

doi:10.2133/dmpk.21.437

Cited by 184 publications

(128 citation statements)

References 176 publications

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“…Nrf2 is primarily a cytosolic protein due to proteasomal degradation regulated by Keap1 (Jaiswal, 2004;Zhang, 2006). When a cell is undergoing oxidative stress, Nrf2 escapes Keap1-mediated degradation, translocates to the nucleus, binds to ARE sequences within the promoters of target genes, and induces expression of phase I and II metabolizing enzymes and transporters pivotal to the maintenance of oxidative stress-inducing molecules (Jaiswal, 2004;Nakata et al, 2006;Zhang, 2006). Such enzymes include NAD(P)H:quinone oxidoreductase-1 (NQO1), glutathione transferase (GST) isoforms, and glutamate cysteine ligase (GCL) subunits (Itoh et al, 1997;Nguyen et al, 2000;Nakata et al, 2006).…”

Section: Introductionmentioning

confidence: 99%

Diversity in Antioxidant Response Enzymes in Progressive Stages of Human Nonalcoholic Fatty Liver Disease

et al. 2010

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ABSTRACT:Nonalcoholic fatty liver disease (NAFLD), which occurs in approximately 17 to 40% of Americans, encompasses progressive stages of liver damage ranging from steatosis to nonalcoholic steatohepatitis (NASH). Inflammation and oxidative stress are known characteristics of NAFLD; however, the precise mechanisms occurring during disease progression remain unclear. The purpose of the current study was to determine whether the expression or function of enzymes involved in the antioxidant response, NAD(P)H:quinone oxidoreductase 1 (NQO1), glutathione transferase (GST), and glutamate cysteine ligase, are altered in the progression of human NAFLD. Human livers staged as normal, steatotic, NASH (fatty), and NASH (not fatty) were obtained from the Liver Tissue Cell Distribution System. NQO1 mRNA, protein, and activity tended to increase with disease progression. mRNA levels of the GST isoforms A1, A2, A4, M3, and P1 increased with NAFLD progression. Likewise, GST A and P protein increased with progression; however, GST M protein levels tended to decrease. Of interest, total GST activity toward the substrate 1-chloro-2,4-dinitrobenzene decreased with NAFLD progression. GSH synthesis does not seem to be significantly dysregulated in NAFLD progression; however, the GSH/ oxidized glutathione redox ratio seemed to be reduced with disease severity, indicating the presence of oxidative stress and depletion of GSH throughout progression of NAFLD. Malondialdehyde concentrations were significantly increased with disease progression, further indicating the presence of oxidative stress. Nuclear immunohistochemical staining of nuclear factor E2-related factor 2 (Nrf2), an indicator of activation of the transcription factor, was evident in all stages of NAFLD. The current data suggest that Nrf2 activation occurs in response to disease progression followed by induction of specific Nrf2 targets, whereas functionality of specific antioxidant defense enzymes seems to be impaired as NAFLD progresses.

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Section: Introductionmentioning

confidence: 99%

Diversity in Antioxidant Response Enzymes in Progressive Stages of Human Nonalcoholic Fatty Liver Disease

et al. 2010

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“…Interestingly, PPAR and Nrf2 are known to be coregulated (Kang et al 2005) and cross-talk between Nrf2 and PXR through their partner retinoid X receptor (RXR) is to be expected (Lu 2009). It is well-established that nuclear receptors can have cross-talk by sharing binding affinities for the same ligands, DNA responsive elements, partners during heterodimerization, cellular functions, or sharing co-factors (Nakata et al 2006;Kohle and Bock 2009). Taken together, this indicates that MDMA-induced toxicity may arise from a complex mechanism that can involve several nuclear receptors, metabolizing enzymes, and multiple cell types (Figure 2).…”

Section: Nuclear Receptors and Mdma-mediated Hepatotoxicitymentioning

confidence: 97%

A mechanistic insight into 3,4-methylenedioxymethamphetamine (“ecstasy”)-mediated hepatotoxicity

Antolino-Lobo

Meulenbelt

Berg

et al. 2011

Veterinary Quarterly

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3,4-Methylenedioxymethamphetamine (MDMA, ''ecstasy'') is a popular drug of abuse among young people with stimulant and hallucinogenic properties. The drug is generally thought to be safe among consumers due to its low-mortality rates. However, MDMA-adverse effects can occur and the risks are not clearly associated to a specific pattern since the consumption quantity seems not to be correlated with the initiation and severity of the injury. MDMA-mediated adverse health effects have been widely studied and can be evoked by multiple factors such as hyperthermia, polydrug abuse (drug-drug interactions), the altered release of neurotransmitters, impairment of mitochondrial function and apoptosis, metabolism and immune responses. Another adverse effect often associated with MDMA is liver toxicity, yet the mechanism of MDMA-induced liver toxicity is not completely understood. A critical starting point appears to be the hepatic metabolism of MDMA by phase I and II enzymes, leading to reactive metabolites. Elucidating the mechanism of hepatic injury mediated by MDMA is of high toxicological and clinical relevance. In this review, an overview of the literature and the latest findings with respect to the mechanism of MDMA-mediated liver toxicity is described.

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“…These genes were representative drug metabolizing genes those expressions were regulated by AHR (Whitlock 1999;Nakata et al 2006). The stable AHR-responsive HepG2 cells were seeded onto a pre-coated 24-well cell culture plate at a density of 1 9 10 5 cells/well.…”

Section: Isolation Of Total Rna and Real-time Pcrmentioning

confidence: 99%

“…Dose-dependent effects were analyzed using Tukey multiple comparison test with oneway ANOVA. Time-course changes in the mRNA level of the AHR-target genes in stably transfected HepG2 cells after 3MC treatment CYP1A1, UGT1A1 and ABCG 2 were known as representative target genes of AHR (Whitlock 1999;Nakata et al 2006). We detected the mRNA expression of these genes to estimate AHR transcriptional activity.…”

Section: Construction Of a Stable Ahr-responsive Hepg2 Cell Linementioning

confidence: 99%

“…AHR belongs to the basic helix-loophelix/Per-Arnt-Sim (bHLH/PAS) family and translocates into the nucleus and heterodimerizes with another bHLH/PAS protein, aryl hydrocarbon nuclear translocator (ARNT) (Crews 1998). This AHR/ARNT complex binds to specific enhancer sequences adjacent to target promoters termed xenobiotic responsive elements (XREs) and enhances the transcription of target genes encoding phase 1 metabolic enzymes such as the cytchrome P450 family (CYP) 1A1 and CYP1A2, phase 2 metabolic enzymes such as uridine diphosphate glucuronosyltransferase (UGT) 1A1 and UGT1A6, and phase 3 metabolic enzymes such as the ATP-binding cassette (ABC) transporter, subfamily G, member 2 (ABCG2) (Whitlock 1999;Nakata et al 2006). Therefore, AHR was originally regarded as a key regulator of xenobiotic metabolism.…”

Section: Introductionmentioning

confidence: 99%

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Establishment of a stable aryl hydrocarbon receptor-responsive HepG2 cell line

Satsu

Yoshida²,

Mikubo

et al. 2014

Cytotechnology

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The aryl hydrocarbon receptor (AHR) is a ligand-dependent transcription factor. It heterodimerizes with aryl hydrocarbon nuclear translocator, binds to the xenobiotic-responsive element (XRE), and enhances the transcription of genes encoding xenobiotic metabolizing enzymes. AHR also plays important roles in the inhibition of intestinal carcinogenesis and the modulation of gut immunity. It is very important to screen for AHR-activating compounds because those are expected to produce the AHR-mediated physiological functions. Until now, AHR-mediated transcriptional activity represented by the transcriptional activity of CYP1A1 in luciferase assay has been applied as a screening procedure for AHR-activating compounds. However, the AHR-mediated transcriptional activity did not necessarily correspond with the CYP1A1 transcriptional activity. To evaluate AHRmediated transcriptional activity more specifically, and to screen for AHR-activating compounds, we establish a stable AHR-responsive HepG2 cell line by co-transfection of an AHR expression vector and an AHR-responsive vector (pGL3-XRE) containing a luciferase gene and three tandemly arranged XRE elements into a human hepatoma derived cell line, HepG2. The induction of luciferase activity in the stable AHR-responsive HepG2 cell line by typical AHR activators occurred in time-and concentrationdependent manners. By assessing the AHR target genes CYP1A1, UGT1A1, and ABCG2, an AHR activator-mediated induction was observed at mRNA level. Furthermore, the AHR activator-mediated induction of luciferase activity was positively correlated with the mRNA levels of CYP1A1, UGT1A1, and ABCG2. These findings verified the usefulness of the established stable AHR-responsive HepG2 cell line for the screening of AHR-activating compounds.

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Nuclear Receptor-Mediated Transcriptional Regulation in Phase I, II, and III Xenobiotic Metabolizing Systems

Cited by 184 publications

References 176 publications

Diversity in Antioxidant Response Enzymes in Progressive Stages of Human Nonalcoholic Fatty Liver Disease

Diversity in Antioxidant Response Enzymes in Progressive Stages of Human Nonalcoholic Fatty Liver Disease

A mechanistic insight into 3,4-methylenedioxymethamphetamine (“ecstasy”)-mediated hepatotoxicity

Establishment of a stable aryl hydrocarbon receptor-responsive HepG2 cell line

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