Induction of cell proliferation in the rat liver by the short-term administration of ethyl &lt;i&gt;tertiary&lt;/i&gt;-butyl ether

Kakehashi, Anna; Hagiwara, Akeo; Imai, Norio; Wei, Min; Fukushima, Shoji; Wanibuchi, Hideki

doi:10.1293/tox.2014-0056

Cited by 7 publications

(5 citation statements)

References 18 publications

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“…In addition, 5-bromo-2’-deoxy-uridine labeling indices in hepatocytes were found to be significantly increased in rats exposed to ETBE in an inhalation toxicity study 14 . Recently, the possible mode of action (MOA) for ETBE hepatotumorigenicity in rats was investigated, and the results indicated that liver tumor development could be related to induction of cell proliferation due to induction of oxidative stress and DNA modifications, which depend on activation of constitutive androstane receptor, pregnane-X-receptor and peroxisome proliferator-activated receptors 15 , 16 . The available evidence thus strongly indicates that stimulation of cell proliferation is involved in liver tumor-promoting effects of ETBE 15 , 16 .…”

Section: Discussionmentioning

confidence: 99%

Promotion of liver and kidney carcinogenesis by ethyl <i>tertiary</i>-butyl ether (ETBE) in male Wistar rats

Hagiwara¹,

Doi²,

Imai³

et al. 2015

J Toxicol Pathol

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Tumor-promoting effects of ethyl tertiary-butyl ether (ETBE) were investigated in a 2-stage carcinogenesis bioassay with regard to hepatic and renal carcinogenesis in rats. Male 6-week-old Wistar rats were given drinking water containing N-ethyl-N-(2-hydroxyethyl)nitrosamine (EHEN), as an initiator, at a dose of 500 ppm for 2 weeks. Starting one week thereafter, the animals were administered ETBE at dose levels of 0 (control), 100, 300, 500 or 1,000 mg/kg/day by gavage for 19 weeks from week 4 to 22. Necropsy of all rats was performed at week 23, and livers and kidneys were examined histopathologically. Incidences of hepatocellular adenomas, and those of combined hepatocellular adenomas and carcinomas were significantly elevated in rats given 1,000 mg/kg/day ETBE, but not 100‒500 mg/kg/day ETBE, and there was a significant increase in the average numbers of lesions. No significant differences in incidences and average numbers of renal tubule neoplasms were found in rats administered 100‒1,000 mg/kg/day ETBE. However, the average numbers of atypical tubule hyperplasias, considered to be preneoplastic lesions, were significantly increased in rats given ETBE at 1,000 mg/kg/day, but not in rats given 500 mg/kg/day or lower doses. Thus, these results imply that ETBE has hepatic and renal tumor-promoting activities that affect EHEN-induced carcinogenesis in male rats, and the no-observed-effect level is 500 mg/kg/day under the present experimental conditions.

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Section: Discussionmentioning

confidence: 99%

Promotion of liver and kidney carcinogenesis by ethyl <i>tertiary</i>-butyl ether (ETBE) in male Wistar rats

Hagiwara¹,

Doi²,

Imai³

et al. 2015

J Toxicol Pathol

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“…This observation further confirms that ETBE is not an initiator of liver tumorigenesis and thus is not likely a mutagenic carcinogen. The tumor promotion activity of ETBE is likely related to the induction of cell proliferation as reported by Kakehashi et al (2013Kakehashi et al ( , 2016.…”

Section: Discussionmentioning

confidence: 59%

Investigation of the potential mutagenicity of ethyl tertiary‐butyl ether in the tumor target tissue using transgenic Big Blue Fischer 344 rats following whole body inhalation exposure

Gollapudi¹,

Rushton²

2023

Environ and Mol Mutagen

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Ethyl tertiary‐butyl ether (ETBE) is a fuel oxygenate used for the efficiency of motor vehicle fuels and their octane ratings. ETBE has been reported to induce liver adenomas in male rats in a 2‐year bioassay at the highest inhalation concentration tested of 5000 ppm. To investigate the potential mutagenicity of ETBE in the liver, male Big Blue Fischer 344 rats were exposed for 28 consecutive days (6 h/day) to 0, 500, 1500, and 5000 ppm ETBE. The treated rats were sacrificed 3 days post‐exposure and the frequencies of cII mutants were evaluated in the liver and bone marrow tissues. The mutant frequency (MF) of the liver in the negative control group was 36.3 × 10−6 and this value was not significantly different in ETBE‐exposed animals (39.4, 37.3, and 45.9 × 10−6 in 500, 1500, and 5000 ppm groups, respectively). In the bone marrow, the mean MF in the negative control was 32.9 × 10−6 which was not different from the means of the exposed groups (33.8, 22.6, and 32.0 × 10−6 for groups exposed to 500, 1500 and 5000 ppm, respectively). These data, along with consistent negative response reported in the literature for other apical genotoxicity endpoints informs that mutagenicity is not likely the initial key event in the mode of action for ETBE‐induced hepatocarcinogenesis in the rat.

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“…In several studies that focused on the identification of the mode of action for the ETBE-induced liver tumors in rats, Kakehashi et al (2013Kakehashi et al ( , 2015 provided evidence to support a high-dose mode of action similar to that of phenobarbital: induction of cell proliferation due to oxidative stress and DNA modification-dependent activation of receptors, including constitutive androstane receptor, pregnane-X-receptor and peroxisome proliferator-activated receptors. This mode of action for liver tumors in rats is considered not to be operative in humans (Kakehashi et al, 2013).…”

Section: Discussionmentioning

confidence: 99%

Physiologically based pharmacokinetic model for ethyl tertiary‐butyl ether and tertiary‐butyl alcohol in rats: Contribution of binding to α2u–globulin in male rats and high‐exposure nonlinear kinetics to toxicity and cancer outcomes

Borghoff

Ring

Banton

et al. 2016

J of Applied Toxicology

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In cancer bioassays, inhalation, but not drinking water exposure to ethyl tertiary‐butyl ether (ETBE), caused liver tumors in male rats, while tertiary‐butyl alcohol (TBA), an ETBE metabolite, caused kidney tumors in male rats following exposure via drinking water. To understand the contribution of ETBE and TBA kinetics under varying exposure scenarios to these tumor responses, a physiologically based pharmacokinetic model was developed based on a previously published model for methyl tertiary‐butyl ether, a structurally similar chemical, and verified against the literature and study report data. The model included ETBE and TBA binding to the male rat‐specific protein α2u–globulin, which plays a role in the ETBE and TBA kidney response observed in male rats. Metabolism of ETBE and TBA was described as a single, saturable pathway in the liver. The model predicted similar kidney AUC0–∞ for TBA for various exposure scenarios from ETBE and TBA cancer bioassays, supporting a male‐rat‐specific mode of action for TBA‐induced kidney tumors. The model also predicted nonlinear kinetics at ETBE inhalation exposure concentrations above ~2000 ppm, based on blood AUC0–∞ for ETBE and TBA. The shift from linear to nonlinear kinetics at exposure concentrations below the concentration associated with liver tumors in rats (5000 ppm) suggests the mode of action for liver tumors operates under nonlinear kinetics following chronic exposure and is not relevant for assessing human risk. Copyright © 2016 The Authors Journal of Applied Toxicology Published by John Wiley & Sons Ltd

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Induction of cell proliferation in the rat liver by the short-term administration of ethyl <i>tertiary</i>-butyl ether

Cited by 7 publications

References 18 publications

Promotion of liver and kidney carcinogenesis by ethyl <i>tertiary</i>-butyl ether (ETBE) in male Wistar rats

Promotion of liver and kidney carcinogenesis by ethyl <i>tertiary</i>-butyl ether (ETBE) in male Wistar rats

Investigation of the potential mutagenicity of ethyl tertiary‐butyl ether in the tumor target tissue using transgenic Big Blue Fischer 344 rats following whole body inhalation exposure

Physiologically based pharmacokinetic model for ethyl tertiary‐butyl ether and tertiary‐butyl alcohol in rats: Contribution of binding to α2u–globulin in male rats and high‐exposure nonlinear kinetics to toxicity and cancer outcomes

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