Super-induced gene expression of the N-methyl-D-aspartate receptor 2C subunit in chemical-induced hypertrophic liver in rats

Nemoto, Kiyomitsu; Tanaka, Takahiro; Ikeda, Ayaka; Ito, Sei; Mizukami, Masanori; Hikida, Tokihiro; Gamou, Toshie; Habano, Wataru; Ozawa, Shogo; Inoue, Kaoru; Yoshida, Midori; Nishikawa, Akiyoshi; Degawa, Masakuni

doi:10.2131/jts.36.507

Cited by 7 publications

(11 citation statements)

References 26 publications

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“…Our previous study showed that well known non-genotoxic hepato-tumorigenetic agents including PB, CF (a peroxisome proliferator), and PBO (a pesticide synergist), induce hepatic hypertrophy (Nemoto et al, 2011). To varying degrees, the increase in liver weight was evident even at day 3 in all of the groups.…”

Section: Discussionmentioning

confidence: 88%

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Estrogen and androgen receptor status in hepatocellular hypertrophy induced by phenobarbital, clofibrate, and piperonyl butoxide in F344 rats

et al. 2012

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-The present study examined hepatic estrogen receptor (ER) and androgen receptor (AR) levels as well as estrogen-signaling status in a model of rat hepatic hypertrophy induced by phenobarbital (PB), chlofibrate (CF), or piperonyl butoxide (PBO). Male F344 rats were fed with PB at 2,500 ppm, CF at 2,500 ppm, and PBO at 20,000 ppm for 3 days, 4 weeks, and 13 weeks. CF and PBO induced diffuse hypertrophy, while centrilobular hypertrophy was observed with PB administration. The levels of mRNA for ERα, AR and leukemia inhibitory factor receptor (LIFR) which was found to be estrogen responsive in the present study, were determined by quantitative RT-PCR. In the CF and PBO groups, ERα mRNA expression was reduced, and consequently, the expression of a responsive gene, LIFR, was also decreased, while PB had no effect on ER mRNA levels. AR mRNA expression decreased in all the treated groups, but reduction was persistent only in PB group. Recently, LIFR was identified as a tumor suppressor gene in human HCC. Thus, LIFR may be one of the key mediators of hepatic carcinogenesis induced by CF and PBO, but PB appears to act via different mechanisms.

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Section: Discussionmentioning

confidence: 88%

“…An animal experiment feeding of PB, CF and BPO was previously reported (Nemoto et al, 2011) and the same liver samples were shared in the present study. Briefly, six week-old male F344/DuCrj rats were fed with PB, CF and PBO in diet at concentrations of 2500, 2500 and 20,000 ppm, respectively.…”

Section: Animal Experimentsmentioning

confidence: 78%

Estrogen and androgen receptor status in hepatocellular hypertrophy induced by phenobarbital, clofibrate, and piperonyl butoxide in F344 rats

et al. 2012

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“…We previously reported that these compounds regulate the expression of various genes involved in DNA damage and hormone receptors other than metabolic enzymes (32)(33)(34)(35). However, we have yet to identify the genes linking hepatic potency and elevated mutations, and more speciˆcally, we have yet to account for the fact that the most hypertrophic compound (PBO) was not the most eŠective compound (DBDE) in enhancing mutations.…”

Section: Discussionmentioning

confidence: 99%

Effects of Oral Administration of Non-genotoxic Hepato-hypertrophic Compounds on Metabolic Potency of Rat Liver

Fang

Nunoshiba²,

Yoshida³

et al. 2014

Genes and Environment

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It remains uncertain why non-genotoxic compounds that result in liver hypertrophy cause liver tumors. In an eŠort to resolve this issue, we examined whether liver postmitochondrial fraction (S9) prepared from rats treated with non-genotoxic compounds aŠected the genotoxicity of pro-mutagens. Known hepatotoxic compounds, such as piperonyl butoxide (PBO), decabromodiphenyl ether (DBDE), beta-naphtho‰avone (BNF), indole-3-carbinol (I3C) and acetaminophen (AA), were orally administered to male and female F344 rats at doses su‹cient to cause liver hypertrophy. Rats received diets containing each test compound for 3 days, 4 weeks or 13 weeks, and were then kept for 4 weeks without the test chemical. S9 prepared from the livers of each group was used for the Ames test with 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx), benzo[a]pyrene (BaP) and N-nitrosodimethylamine (NDMA). In both sexes, liver hypertrophy was observed following administration of all test compounds, and was then reversed to the control state when administration ceased. The mutagenicity of MeIQx, BaP and NDMA increased with the use of S9 derived from rats treated with non-genotoxic compounds other than AA. DBDE administration had a marked eŠect on the mutagenicity of BaP (over a 30-fold increase in females) and NDMA (about a 20-fold increase in males). To estimate the involvement of metabolic enzymes in the alteration of mutagenicity, we measured the activity of ethoxyresoruˆn-O-deethylase (EROD) and methoxyresoruˆn-O-demethylase (MROD) (phase I enzymes), and UDP-glucuronosyltransferase (UGT) and glutathione S-transferase (GST) (phase II enzymes) in each S9 sample. The activity of phase I enzymes increased, even at the 3rd day following administration, and then decreased gradually, except in the case of AA, while the activity of phase II enzymes increased slightly. These results suggest that non-genotoxic hepato-hypertrophic compounds may be partly involved in carcinogenesis by modulating the metabolism of pre-carcinogens incorporated from the environment, in a manner that is dependent on sex and pre-incorporated chemicals.

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“…Conventional RT-PCR using gel electrophoresis and real-time RT-PCR were performed as described previously (Nemoto et al, 2011).…”

Section: Rt-pcr Analysismentioning

confidence: 99%

“…We have recently reported super-induced expression of the Grin2c gene encoding an NMDA receptor 2C subunit during rat liver enlargement with hepatocellular hypertrophy induced by phenobarbital (PB), clofibrate (CF), or piperonyl butoxide (PBO) (Nemoto et al, 2011), or with hyperplasia induced by lead nitrate (LN) (Nemoto et al, 2013). Our interest has therefore expanded to whether chemicals possessing the capacity to induce liver enlargement commonly lead to such induced expression and how types of chemical-induced hepatic functional and morphological changes accompany such induced expression.…”

Section: Introductionmentioning

confidence: 99%

Change in the gene expression of the <i>N</i>-methyl-D-aspartate receptor 2C subunit by dietary β-naphthoflavone, indole-3-carbinol, or acetaminophen in the rat liver

et al. 2013

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-We have previously demonstrated super-induced expression of the Grin2c gene encoding the N-methyl-D-aspartate receptor 2C subunit during the process of liver enlargement induced by phenobarbital, clofibrate, piperonyl butoxide, or lead nitrate. In the present study, hepatic Grin2c gene expression levels were assessed by real-time RT-PCR in male F344 rats fed for 3 days, 4 weeks, and 13 weeks a diet containing either β-naphthoflavone (BNF) (5,000 ppm), indole-3-carbinol (I3C) (2,000 ppm), or acetaminophen (AA) (12,500 ppm until the first 14 days; 10,000 ppm from 15 days on), each of which is capable of inducing hepatocellular hypertrophy. Especially, either the 4-week or the 13-week treatment with each chemical, except for BNF, resulted in a drastic increase in the expression level of the Grin2c gene. DNA microarray analysis using RNAs of 13-week-treated rats showed that in the I3C-and AA-treated rats, the fold-increase rates of the Grin2c gene ranked second and first, respectively, among the genes analyzed. Histopathological analyses indicated that the slight hepatocellular hypertrophy in the periportal area and the hepatocellular necrosis in a portion of the centrilobular area developed in the BNF-treated and AA-treated rats, respectively. In addition, relative liver weight was significantly higher in the rats treated with BNF and I3C than in the control rats. The present findings suggest the possibility that the induction of Grin2c gene expression is not necessarily dependent on only the development of liver enlargement, although the significance of this induction remains unclear.

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Super-induced gene expression of the N-methyl-D-aspartate receptor 2C subunit in chemical-induced hypertrophic liver in rats

Cited by 7 publications

References 26 publications

Estrogen and androgen receptor status in hepatocellular hypertrophy induced by phenobarbital, clofibrate, and piperonyl butoxide in F344 rats

Estrogen and androgen receptor status in hepatocellular hypertrophy induced by phenobarbital, clofibrate, and piperonyl butoxide in F344 rats

Effects of Oral Administration of Non-genotoxic Hepato-hypertrophic Compounds on Metabolic Potency of Rat Liver

Change in the gene expression of the <i>N</i>-methyl-D-aspartate receptor 2C subunit by dietary β-naphthoflavone, indole-3-carbinol, or acetaminophen in the rat liver

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