Mode of action of ethyl tertiary-butyl ether hepatotumorigenicity in the rat: evidence for a role of oxidative stress via activation of CAR, PXR and PPAR signaling pathways
Kakehashi, A; Hagiwara, A; Imai, N; Nagano, K; Nishimaki, F; Banton, M; Wei, M; Fukushima, S; Wanibuchi, H
HERO ID
2321104
Reference Type
Journal Article
Year
2013
Language
English
PMID
| HERO ID | 2321104 |
|---|---|
| In Press | No |
| Year | 2013 |
| Title | Mode of action of ethyl tertiary-butyl ether hepatotumorigenicity in the rat: evidence for a role of oxidative stress via activation of CAR, PXR and PPAR signaling pathways |
| Authors | Kakehashi, A; Hagiwara, A; Imai, N; Nagano, K; Nishimaki, F; Banton, M; Wei, M; Fukushima, S; Wanibuchi, H |
| Journal | Toxicology and Applied Pharmacology |
| Volume | 273 |
| Issue | 2 |
| Page Numbers | 390-400 |
| Abstract | To elucidate possible mode of action (MOA) and human relevance of hepatotumorigenicity in rats for ethyl tertiary-butyl ether (ETBE), male F344 rats were administered ETBE at doses of 0, 150 and 1000 mg/kg body weight twice a day by gavage for 1 and 2 weeks. For comparison, non-genotoxic carcinogen phenobarbital (PB) was applied at a dose of 500 ppm in diet. Significant increase of P450 total content and hydroxyl radical levels by low, high doses of ETBE and PB treatments at weeks 1 and 2, and 8-OHdG formation at week 2, accompanied accumulation of CYP2B1/2B2, CYP3A1/3A2 and CYP2C6, and downregulation of DNA oxoguanine glycosylase 1, induction of apoptosis and cell cycle arrest in hepatocytes, respectively. Up-regulation of CYP2E1 and CYP1A1 at weeks 1 and 2, and peroxisome proliferation at week 2 were found in high dose ETBE group. Results of proteome analysis predicted activation of upstream regulators of gene expression altered by ETBE including constitutive androstane receptor (CAR), pregnane-X-receptor (PXR) and peroxisome proliferator-activated receptors (PPARs). These results indicate that the MOA of ETBE hepatotumorigenicity in rats may be related to induction of oxidative stress, 8-OHdG formation, subsequent cell cycle arrest, and apoptosis, suggesting regenerative cell proliferation after week 2, predominantly via activation of CAR and PXR nuclear receptors by a mechanism similar to that of PB, and differentially by activation of PPARs. The MOA for ETBE hepatotumorigenicity in rats is unlikely to be relevant to humans. |
| Doi | 10.1016/j.taap.2013.09.016 |
| Pmid | 24090815 |
| Wosid | WOS:000328099500015 |
| Is Certified Translation | No |
| Dupe Override | No |
| Comments | Journal: ISSN: |
| Is Public | Yes |
| Language Text | English |