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Toxicol Lett. 2017 Jul 5;276:138-143. doi: 10.1016/j.toxlet.2017.05.006. Epub 2017 May 8.

Mode of action and human relevance of THF-induced mouse liver tumors.

Author information

1
Ashland, Inc., 1005 U.S. Highway 202/206, Bridgewater, NJ 08807, USA. Electronic address: CJChoi@ashland.com.
2
LyondellBasell, Delftsplein 27E, 3013 AA, Rotterdam, The Netherlands. Electronic address: erik.rushton@LYB.com.
3
Concept Life Sciences, 2 James Lindsay Place, Dundee Technopole, Dundee DD1 5JJ, Scotland, United Kingdom. Electronic address: Audrey.Vardy@conceptlifesciences.com.
4
Concept Life Sciences, 2 James Lindsay Place, Dundee Technopole, Dundee DD1 5JJ, Scotland, United Kingdom. Electronic address: Larry.Higgins@conceptlifesciences.com.
5
Concept Life Sciences, 2 James Lindsay Place, Dundee Technopole, Dundee DD1 5JJ, Scotland, United Kingdom. Electronic address: Andrea.Augello@conceptlifesciences.com.
6
BASF Corporation, 1609 Biddle Avenue, DZ 40, Wyandotte, MI 48192, USA. Electronic address: ralph.parod@basf.com.

Abstract

In a National Toxicology Program (NTP) bioassay, inhalation of tetrahydrofuran (THF) induced liver tumors in female B6C3F1 mice but not in male mice or rats of either sex. Since THF is not genotoxic, the NTP concluded this carcinogenic activity was likely mediated via non-genotoxic modes of action (MOA). Based on evidence that THF and phenobarbital share a similar MOA, female Car/Pxr knock-out mice were orally exposed to THF to evaluate the potential role of CAR activation in the MOA for THF-induced liver tumors. Because data from this oral study with Car/Pxr knock-out mice (C57Bl/6) and the inhalation studies with wild type mice (B6C3F1) reported by NTP and others were derived from different strains, oral studies with wild type B6C3F1 and C57Bl/6 mice were conducted to ensure THF responses in both strains were comparable. As seen in inhalation studies with THF, oral exposure of wild type female mice to a maximum tolerated dose of THF increased total P450 content, CAR-related P450 activities, and hepatocyte proliferation; these effects were not observed in Car/Pxr knock-out female mice. This finding supports the hypothesis THF-induced carcinogenicity is likely mediated via CAR activation that has limited, if any, relevance to humans.

KEYWORDS:

Car/Pxr knockout mouse; Constitutive androstane receptor (CAR); Human relevance; Liver tumors; Mode of action; Tetrahydrofuran (THF)

PMID:
28495613
DOI:
10.1016/j.toxlet.2017.05.006
[Indexed for MEDLINE]
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