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

Fujimoto, Nariaki; Inoue, Kaoru; Yoshida, Midori; Nishikawa, Akiyoshi; Ozawa, Shogo; Gamou, Toshie; Nemoto, Kiyomitsu; Degawa, Masakuni

doi:10.2131/jts.37.281

Cited by 7 publications

(4 citation statements)

References 32 publications

(31 reference statements)

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“…The female-specifically expressed gene Lifr in ZSF1 liver is an integral component of the glycoprotein-LIFR signaling complex, acts as signal receptor for cytokine leukemia inhibitory factor and other cytokines, and is an estrogen-responsive gene [44]. Our result shows that hepatic Lifr mRNA level was significantly lower in the livers of obese compared to lean females.…”

Section: Discussionmentioning

confidence: 61%

Next generation sequencing of sex-specific genes in the livers of obese ZSF1 rats

et al. 2015

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Type 2 diabetes induces pathophysiological changes in the liver. The aim of this study was to identify differently expressed genes in the livers of male and female ZSF1 rats (ZDFxSHHF-hybrid, generation F1), a model for type 2 diabetes. Gene expression was investigated using next-generation sequencing (NGS). Selected candidate genes were verified by real-time PCR in the livers of obese and lean rats. 103 sex-different genes, associated to pathways "response to chemical stimulus", "lipid metabolism", and "response to organic substance", were identified. Male-specific genes were involved in hepatic metabolism, detoxification, and secretion, e.g. cytochrome P450 2c11 (Cyp2c11), Cyp4a2, glutathione S-transferases mu 2 (Gstm2), and Slc22a8 (organic anion transporter 3, Oat3). Most female-specific genes were associated to lipid metabolism (e.g. glycerol-3-phosphate acyltransferase 1, Gpam) or glycolysis (e.g. glucokinase, Gck). Our data suggest the necessity to pay attention to sex- and diabetes-dependent changes in pre-clinical testing of hepatic metabolized and secreted drugs.

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Section: Discussionmentioning

confidence: 61%

Next generation sequencing of sex-specific genes in the livers of obese ZSF1 rats

et al. 2015

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“…The peroxisomal proliferator response and cytochrome P450 induction associated with PPARa activation probably also explains the greater liver weight associated with increasing dietary MCT since liver hypertrophy is generally associated with this response. 36 Several studies have shown that MCFAs have low-binding affinity for the PPARs; 37,38 therefore, it is likely that PPARa activation by MCT is indirect, and this mechanism will be pursued in future studies.…”

Section: Discussionmentioning

confidence: 99%

Medium chain triglycerides dose-dependently prevent liver pathology in a rat model of non-alcoholic fatty liver disease

Ronis

Baumgardner

Sharma

et al. 2013

Exp Biol Med (Maywood)

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Metabolic syndrome is often accompanied by development of hepatic steatosis and less frequently by non-alcoholic fatty liver disease (NAFLD) leading to non-alcoholic steatohepatitis (NASH). Replacement of corn oil with medium chain triacylglycerols (MCT) in the diets of alcohol-fed rats has been shown to protect against steatosis and alcoholic liver injury. The current study was designed to determine if a similar beneficial effect of MCT occurs in a rat model of NAFLD. Groups of male rats were isocalorically overfed diets containing 10%, 35% or 70% total energy as corn oil or a 70% fat diet in which corn oil was replaced with increasing concentrations of saturated fat (18:82, beef tallow:MCT oil) from 20% to 65% for 21 days using total enteral nutrition (TEN). As dietary content of corn oil increased, hepatic steatosis and serum alanine amino transferases were elevated (P < 0.05). This was accompanied by greater expression of cytochrome P450 enzyme CYP2E1 (P < 0.05) and higher concentrations of polyunsaturated 18:2 and 20:4 fatty acids (FA) in the hepatic lipid fractions (P < 0.05). Keeping the total dietary fat at 70%, but increasing the proportion of MCT-enriched saturated fat resulted in a dose-dependent reduction in steatosis and necrosis without affecting CYP2E1 induction. There was no incorporation of C8-C10 FAs into liver lipids, but increasing the ratio of MCT to corn oil: reduced liver lipid 18:2 and 20:4 concentrations; reduced membrane susceptibility to radical attack; stimulated FA β- and ω-oxidation as a result of activation of peroxisomal proliferator activated receptor (PPAR)α, and appeared to increase mitochondrial respiration through complex III. These data suggest that replacing unsaturated fats like corn oil with MCT oil in the diet could be utilized as a potential treatment for NAFLD.

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

Cited by 7 publications

References 32 publications

Next generation sequencing of sex-specific genes in the livers of obese ZSF1 rats

Next generation sequencing of sex-specific genes in the livers of obese ZSF1 rats

Medium chain triglycerides dose-dependently prevent liver pathology in a rat model of non-alcoholic fatty liver disease

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

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