Transcriptional Regulation of Cytochrome P450 Genes

Fraser, Emily Anne; Henderson, Colin J.; Wolf, Charles

doi:10.1002/9780470921920.edm008

Cited by 2 publications

(1 citation statement)

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“…It was suggested that the induction of AhR genes and EROD activity by phenobarbital attributed more to CAR rather than AhR‐dependent activation (Geter et al , ). In addition, cross‐talk between the CAR and AhR receptors where activation of one receptor can lead to the upregulation of the other receptor‐related genes and activity (Fraser et al , ; Patel et al , ). Taken together, the evidence suggested that toxaphene induces liver tumors in mice through a non‐genotoxic mode of action through either the CAR and/or PXR receptor activation.…”

Section: Discussionmentioning

confidence: 99%

Toxaphene-induced mouse liver tumorigenesis is mediated by the constitutive androstane receptor

Wang

et al. 2017

J. Appl. Toxicol.

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Toxaphene was shown to increase liver tumor incidence in B6C3F1 mice following chronic dietary exposure. Preliminary evidence supported a role for the constitutive androstane receptor (CAR) in the mode of action of toxaphene-induced mouse liver tumors. However, these results could not rule out a role for the pregnane X receptor (PXR) in liver tumor formation. To define further the nuclear receptors involved in this study, we utilized CAR, PXR and PXR/CAR knockout mice (CAR , PXR and PXR /CAR ) along with the wild-type C57BL/6. In this study CAR-responsive genes Cyp3a11 and Cyp2b10 were induced in the liver of C57BL/6 (wild-type) mice by toxaphene (30-570-fold) (at the carcinogenic dose 320 ppm) and phenobarbital (positive control) (16-420-fold) following 14 days' dietary treatment. In contrast, in CAR mice, no induction of these genes was seen following treatment with either chemical. Cyp3a11 and Cyp2b10 were also induced in PXR mice with toxaphene and phenobarbital but were not changed in treated PXR /CAR mice. Similarly, induction of liver pentoxyresorufin-O-deethylase (CAR activation) activity by toxaphene and phenobarbital was absent in CAR and PXR /CAR mice treated with phenobarbital or toxaphene. Ethoxyresorufin-O-deethylase (EROD, represents aryl hydrocarbon receptor activation) activity in CAR mice treated with toxaphene or phenobarbital was increased compared with untreated control, but lower overall in activity in comparison to the wild-type mouse. Liver EROD activity was also induced by both phenobarbital and toxaphene in the PXR mice but not in the PXR /CAR mice. Toxaphene treatment increased 7-benzyloxyquinoline activity (a marker for PXR activation) in a similar pattern to that seen with pentoxyresorufin-O-deethylase. These observations indicate that EROD and PXR activation are evidence, as expected, of secondary overlap to primary CAR receptor activation. Together, these results definitively show that activation of the CAR nuclear receptor is the mode of action of toxaphene-induced mouse liver tumors. Copyright © 2017 John Wiley & Sons, Ltd.

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Section: Discussionmentioning

confidence: 99%

Toxaphene-induced mouse liver tumorigenesis is mediated by the constitutive androstane receptor

Wang

et al. 2017

J. Appl. Toxicol.

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Mechanistic Investigation of Toxaphene Induced Mouse Liver Tumors

et al. 2015

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Chronic exposure to toxaphene resulted in an increase in liver tumors in B6C3F1 mice. This study was performed to investigate the mode of action of toxaphene induced mouse liver tumors. Following an initial 14 day dietary dose range-finding study in male mice, a mechanistic study (0, 3, 32, and 320 ppm toxaphene in diet for 7, 14, and 28 days of treatment) was performed to examine the potential mechanisms of toxaphene induced mouse liver tumors. Toxaphene induced a significant increase in expression of constitutive androstane receptor (CAR) target genes (Cyp2b10, Cyp3a11) at 32 and 320 ppm toxaphene. aryl hydrocarbon receptor (AhR) target genes (Cyp1a1 and Cyp1a2) were slightly increased in expression at the highest toxaphene dose (320 ppm). No increase in peroxisome proliferator-activated receptor alpha activity or related genes was seen following toxaphene treatment. Lipid peroxidation was seen following treatment with 320 ppm toxaphene. These changes correlated with increases in hepatic DNA synthesis. To confirm the role of CAR in this mode of action, CAR knockout mice (CAR(-/-)) treated with toxaphene confirmed that the induction of CAR responsive genes seen in wild-type mice was abolished following treatment with toxaphene for 14 days. These findings, taken together with previously reported studies, support the mode of action of toxaphene induced mouse liver tumors is through a nongenotoxic mechanism involving primarily a CAR-mediated processes that results in an increase in cell proliferation in the liver, promotes the clonal expansion of preneoplastic lesions leading to adenoma formation.

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Transcriptional Regulation of Cytochrome P450 Genes

Cited by 2 publications

References 191 publications

Toxaphene-induced mouse liver tumorigenesis is mediated by the constitutive androstane receptor

Toxaphene-induced mouse liver tumorigenesis is mediated by the constitutive androstane receptor

Mechanistic Investigation of Toxaphene Induced Mouse Liver Tumors

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