Artigo Revisado por pares

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

2017; Wiley; Volume: 37; Issue: 8 Linguagem: Inglês

10.1002/jat.3445

ISSN

1099-1263

Autores

Zemin Wang, Xilin Li, Qiangen Wu, James C. Lamb, James E. Klaunig,

Tópico(s)

Inflammatory mediators and NSAID effects

Resumo

Journal of Applied ToxicologyVolume 37, Issue 8 p. 967-975 Research article Toxaphene-induced mouse liver tumorigenesis is mediated by the constitutive androstane receptor Zemin Wang, Zemin Wang orcid.org/0000-0003-4189-578X Department of Environmental Health, Indiana University Bloomington, IN, 47405 USASearch for more papers by this authorXilin Li, Xilin Li Department of Environmental Health, Indiana University Bloomington, IN, 47405 USASearch for more papers by this authorQiangen Wu, Qiangen Wu Department of Environmental Health, Indiana University Bloomington, IN, 47405 USASearch for more papers by this authorJames C. Lamb IV, James C. Lamb IV Center for Toxicology and Mechanistic Biology, Exponent Inc., Alexandria, VA, 22314 USASearch for more papers by this authorJames E. Klaunig, Corresponding Author James E. Klaunig jklauni@indiana.edu Department of Environmental Health, Indiana University Bloomington, IN, 47405 USA Correspondence to: James E. Klaunig, PhD, ATS, IATP, Professor, Laboratory of Investigative Toxicology and Pathology, Department of Environmental Health, Indiana University School of Public Health, 1025 E 7th St, Bloomington, IN 47405, USA. E-mail: jklauni@indiana.eduSearch for more papers by this author Zemin Wang, Zemin Wang orcid.org/0000-0003-4189-578X Department of Environmental Health, Indiana University Bloomington, IN, 47405 USASearch for more papers by this authorXilin Li, Xilin Li Department of Environmental Health, Indiana University Bloomington, IN, 47405 USASearch for more papers by this authorQiangen Wu, Qiangen Wu Department of Environmental Health, Indiana University Bloomington, IN, 47405 USASearch for more papers by this authorJames C. Lamb IV, James C. Lamb IV Center for Toxicology and Mechanistic Biology, Exponent Inc., Alexandria, VA, 22314 USASearch for more papers by this authorJames E. Klaunig, Corresponding Author James E. Klaunig jklauni@indiana.edu Department of Environmental Health, Indiana University Bloomington, IN, 47405 USA Correspondence to: James E. Klaunig, PhD, ATS, IATP, Professor, Laboratory of Investigative Toxicology and Pathology, Department of Environmental Health, Indiana University School of Public Health, 1025 E 7th St, Bloomington, IN 47405, USA. E-mail: jklauni@indiana.eduSearch for more papers by this author First published: 20 February 2017 https://doi.org/10.1002/jat.3445Citations: 12Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat Abstract 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. Citing Literature Volume37, Issue8August 2017Pages 967-975 RelatedInformation

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