کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
---|---|---|---|---|
5846573 | 1128489 | 2013 | 11 صفحه PDF | دانلود رایگان |
عنوان انگلیسی مقاله ISI
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
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کلمات کلیدی
موضوعات مرتبط
علوم زیستی و بیوفناوری
علوم محیط زیست
بهداشت، سم شناسی و جهش زایی
پیش نمایش صفحه اول مقاله
چکیده انگلیسی
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 1000Â mg/kg body weight twice a day by gavage for 1 and 2Â weeks. For comparison, non-genotoxic carcinogen phenobarbital (PB) was applied at a dose of 500Â 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.
ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: Toxicology and Applied Pharmacology - Volume 273, Issue 2, 1 December 2013, Pages 390-400
Journal: Toxicology and Applied Pharmacology - Volume 273, Issue 2, 1 December 2013, Pages 390-400
نویسندگان
Anna Kakehashi, Akihiro Hagiwara, Norio Imai, Kasuke Nagano, Fukumi Nishimaki, Marcy Banton, Min Wei, Shoji Fukushima, Hideki Wanibuchi,