Carbaryl, a Carbamate Insecticide, Is a Ligand for the Hepatic Ah (Dioxin) Receptor

Denison, Michael S.; Phelan, D.; Winter, G.M.; Ziccardi, Michael H.

doi:10.1006/taap.1998.9999

Cited by 78 publications

(37 citation statements)

References 35 publications

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“…We speculate that such arylation of AhR by 1,2-NQ may promote the conformational change in AhR involved in its activation. In our preliminary study, we found that non-classical ligands for AhR such as curcumin (Ciolino et al, 1998) were able to bind to proteins as determined by a BPM assay, whereas little appreciable chemical modification of carbaryl (Denison et al, 1998) and oltipraz (Miao et al, 2003) was seen, even at concentrations of 100 μM (Abiko et al, unpublished observation). Further studies are needed to understand the association of the modification capacity of non-classical ligands for AhR with its activation.…”

Section: Discussionmentioning

confidence: 97%

Covalent binding of quinones activates the Ah receptor in Hepa1c1c7 cells

2015

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-Highly reactive quinone species produced by photooxidation and/or metabolic activation of mono-or bi-aromatic hydrocarbons modulate cellular homeostasis and electrophilic signal transduction pathways through the covalent modification of proteins. Polycyclic aromatic hydrocarbons, but not mono-or bi-aromatic hydrocarbons, are well recognized as ligands for the aryl hydrocarbon receptor (AhR). However, quinone species produced from mono-and bi-aromatic hydrocarbons could potentially cause AhR activation. To clarify the AhR response to mono-and bi-aromatic hydrocarbon quinones, we studied Cyp1a1 (cytochrome P450 1A1) induction and AhR activation by these quinones. We detected Cyp1a1 induction during treatment with quinones in Hepa1c1c7 cells, but not their parent compounds. Nine of the twelve quinones with covalent binding capability for proteins induced Cyp1a1. Cyp1a1 induction mediated by 1,2-naphthoquinone (1,2-NQ), 1,4-NQ, 1,4-benzoquinone (1,4-BQ) and tert-butyl-1,4-BQ was suppressed by a specific AhR inhibitor and was not observed in c35 cells, which do not have a functional AhR. These quinones stimulated AhR nuclear translocation and interaction with the AhR nuclear translocator. Interestingly, 1,2-NQ covalently modified AhR, which was detected by an immunoprecipitation assay using a specific antibody against 1,2-NQ, resulting in enhancement of xenobiotic responsive element (XRE)-derived luciferase activity and binding of AhR to the Cyp1a1 promoter region. While mono-and bi-aromatic hydrocarbons are generally believed to be poor ligands for AhR and hence unable to induce Cyp1a1, our study suggests that the quinones of these molecules are able to modify AhR and activate the AhR/XRE pathway, thereby inducing Cyp1a1. Since we previously reported that 1,2-NQ and tert-butyl-1,4-BQ also activate NF-E2-related factor 2, it seems likely that some of quinones are bi-functional inducers for phase-I and phase-II reaction of xenobiotics.

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Section: Discussionmentioning

confidence: 97%

Covalent binding of quinones activates the Ah receptor in Hepa1c1c7 cells

2015

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“…Substances such as omeprazole, primaquine [19] and carbaryl [20] are classified as atypical CYP1A1 inducers; several mechanisms of induction have been proposed for them [21][22][23][24]. All of these inducers, however, have planar structures of two fused rings, and if those rings are joined by another ring formed by the intramolecular hydrogen bonding either before, if possible, or after hydroxylation of the ring by metabolism, they might be able to bind to AhR.…”

Section: -8 -mentioning

confidence: 99%

“…The hydroxylation of these compounds would be possible in vivo, but in an AhR binding assay without a drug-metabolizing mechanism, these compounds would not be hydroxylated and unable to form intramolecular hydrogen bonding and therefore, may not successfully compete for the binding or be a very weak ligand. In fact, Denison et al showed that carbaryl was a very weak AhR ligand by using a low nonsaturating concentration of radiolabeled TCDD in the ligand-binding assay [5,22].…”

Section: -8 -mentioning

confidence: 99%

Induction of cytochrome P450-1A by the equine estrogen equilenin, a new endogenous aryl hydrocarbon receptor ligand

Jinno

Maruyama

Ishizuka

et al. 2006

The Journal of Steroid Biochemistry and Molecular Biology

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Equilenin is one of ten kinds of estrogens that are found in pregnant mares' urine. It has been used extensively for estrogen replacement therapy in postmenopausal women. Typical inducers of the cytochrome P4501A1 (CYP1A1), such as TCDD, benzo(a)pyrene (B(a)P) and 3-methylcholanthrene, have a planar molecular structure in common and bind to the aryl hydrocarbon receptor (AhR). The structure of equilenin differs from classic estrogens by the presence of two additional double bonds in ring B of the steroid nucleus, and it is planar. This structural similarity of equilenin to the typical AhR agonist prompted us to investigate the capability of equilenin to induce CYP1A1 expression. Administration of equilenin to two mouse strains (C57BL and DBA) that exhibit different degrees of responsiveness to an Ah-receptor agonist and showed that equilenin was capable of dose-dependently increasing both the ethoxyresorufin-O-deethylase activity and CYP1a proteins in both strains of mice.Equilenin also induced CYP1A1 mRNA in treated HepG2 cell lines and transcriptional activity in an XRE-directed luciferase reporter gene. Competitive binding studies using C57BL AhR indicated equilenin weakly displaced 3 H-B(a)P from AhR.Together, these data show that equilenin, an equine steroid hormone, served as an AhR ligand in the present study.

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“…These include 2,3,7,8-tetrachlorodibenzo-p-dioxin, biphenyls, polyhalogenated dibenzo-p-dioxins and dibenzofurans (Poland et al, 1976;Waller and McKinney, 1995). However, it was reported that non-classical AhR ligands, such as kynurenine, carbaryl, oltipraz and curcumin, could also induce CYP1A1 through AhR activation (Opitz et al, 2011;Quattrochi and Tukey, 1993;Ciolino et al, 1998;Denison et al, 1998;Miao et al, 2003). In addition, aromatic hydrocarbons with ring numbers of one or two, such as benzenes and naphthalenes, are thought to be poor AhR ligands, except for halogenated naphthalene, which showed ligand activity for AhR (Waller and McKinney, 1995).…”

Section: Introductionmentioning

confidence: 99%

Quinone-mediated induction of cytochrome P450 1A1 in HepG2 cells through increased interaction of aryl hydrocarbon receptor with aryl hydrocarbon receptor nuclear translocator

Abiko

Lin²,

Lee

et al. 2016

J. Toxicol. Sci.

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-While it has long been believed that benzenes and naphthalenes are unable to activate the aryl hydrocarbon receptor (AhR) because they are poor ligands, we recently reported that these quinoid metabolites upregulated cytochrome P450 1A1 (CYP1A1) in Hepa1c1c7 cells (Abiko et al., 2015). In the current study, AhR activation, measured with a bioluminescence-based cell free assay, was induced by 1,2-naphthoquinone (1,2-NQ), a metabolite of naphthalene. Consistent with this, 1,4-benzoquinone (1,4-BQ), tert-butyl-1,4-BQ, and 1,4-NQ, as well as 1,2-NQ, all electrophilic mono-and bi-cyclic quinones, upregulated CYP1A1 mRNA and protein in HepG2 cells, whereas their parent aromatic hydrocarbons had little effect. Furthermore, immunofluorescence analysis confirmed that these quinones enhanced translocation of AhR to the nucleus.

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Carbaryl, a Carbamate Insecticide, Is a Ligand for the Hepatic Ah (Dioxin) Receptor

Cited by 78 publications

References 35 publications

Covalent binding of quinones activates the Ah receptor in Hepa1c1c7 cells

Covalent binding of quinones activates the Ah receptor in Hepa1c1c7 cells

Induction of cytochrome P450-1A by the equine estrogen equilenin, a new endogenous aryl hydrocarbon receptor ligand

Quinone-mediated induction of cytochrome P450 1A1 in HepG2 cells through increased interaction of aryl hydrocarbon receptor with aryl hydrocarbon receptor nuclear translocator

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