Sex and circadian modulatory effects on rat liver as assessed by transcriptome analyses

Hirao, Jun; Nishimura, Masatoshi; Arakawa, Shingo; Niino, Noriyo; Mori, Kazuhiko; Furukawa, Tadashi; Sanbuissho, Atsushi; Manabe, Sunao; Nishihara, Masugi; Mori, Yuji

doi:10.2131/jts.36.9

Cited by 29 publications

(29 citation statements)

References 56 publications

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“…These findings are in line with the high number of hepatic genes, which were reported to be sexdependently expressed in the human and in the rodent (rat and mouse) liver [6,12,13,31]. In addition to sex-dependent genes localized Female-specific genes: negative log2 fold change (log2 FC) and male-specific genes: positive log2FC; FDR-p value: false discovery rate-corrected p-value.…”

Section: Discussionsupporting

confidence: 82%

“…In contrast, sitagliptin transport was shown to be OAT3-mediated [11]. Sex-differences were found for the expression of genes involved in several hepatic drug detoxification and metabolism pathways, in human liver as well as in several rat models for diabetes [6,12,13]. Furthermore, it was postulated that the increased bile acid pool in diabetic rats stimulated the transcription of anion transporters in the sinusoidal membrane of hepatocytes [14].…”

Section: Introductionmentioning

confidence: 99%

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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: Discussionsupporting

confidence: 82%

Section: Introductionmentioning

confidence: 99%

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

et al. 2015

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“…−: Not applicable. P2C11 and CYP3A2 are male-specific or predominant enzymes [3,6,9]. in the present study, cYP2c11 and CYP3A2 were male-specific and predominant enzymes.…”

Section: ± 89supporting

confidence: 61%

“…in the present study, cYP2c11 and CYP3A2 were male-specific and predominant enzymes. cYP3a2 was allocated to relevant biological pathways, which were notably enriched in the metabolism of retinols, xenobiotics, linoleic acid, and others [3]. cYP2c12…”

Section: ± 89mentioning

confidence: 99%

Data on Wistar Hannover Rats from a General Toxicity Study

et al. 2012

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Abstract:The aim of this study was to collect data on chronological changes in clinical laboratory tests, pathological examinations, and hepatic drug-metabolizing enzymes from Wistar Hannover rats at 8, 10, 19, and 32 weeks of age. The serum triglyceride concentration and the serum LDL cholesterol level were higher in males than in females at all ages. In contrast, serum total protein and creatinine concentrations and cholinesterase activity were lower in males than in females. In addition, sex differences were confirmed in pituitary weight and hepatic CYP3A2 and CYP2C11 activities. In conclusion, the general toxicological data noted in clinical laboratory tests, pathological examinations, and hepatic drug-metabolizing enzymes relating to chronological changes and sex differences may be useful in assessing drug-related toxicity in this strain. Key words: clinical laboratory test, hepatic drug-metabolizing enzyme, pathological examination sprague-dawley (sd) and F344 rats are commonly used for toxicity studies in japan [2], and the inbred F344/N rat substrain has been used for the National toxicity Program rodent toxicity and carcinogenicity bioassays for more than thirty years [10,19]. the F344/N rat is known to have high background incidences of certain types of tumor including testicular interstitial cell tumors and mononuclear cell leukemia [7], while typical spontaneous diseases in aged sd rats are chronic nephropathy and pituitary and mammary tumors [5,16]. therefore, the use of these strains in long-term toxicity studies should be carefully considered when planning study design and assessing toxicity.wistar Hannover rats are used widely in Europe [21], particularly for toxicity studies, because of their small body size, long survival rate, low spontaneous tumor incidence, and ease of handling. research with this strain has been limited in japan; however, its use in toxicity studies is expected to increase. in 2006, Petterino et al. reported clinical chemistry and hematology historical control data from preclinical toxicity studies using sd rats [14], but published historical data on wistar Hannover rats relating to a general toxicity study are scarce [21]. Furthermore, age-related changes and sex differences in serum chemistry values in sd rats have been reported [18]. therefore, collection of general toxico-

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“…C/EBPα transactivates many liver-specific genes such as albumin and the enzymes in the urea cycle (Tan et al, 2007). HNF4α is a highly conserved member of the nuclear receptor superfamily (NR2A1) and it regulates multiple liver functions, including lipid homeostasis, lipoprotein production and bile acid biosynthesis (Hirao et al, 2011). HNF4α has been also shown to be a critical factor for the expression of many major drug-metabolizing CYP genes, including CYP2B6, CYP2D6 and CYP3A4 (Benet et al, 2010).…”

Section: Discussionmentioning

confidence: 99%

Expression of albumin and cytochrome P450 enzymes in HepG2 cells cultured with a nanotechnology-based culture plate with microfabricated scaffold

Nakamura¹,

Kato²,

Aizawa³

et al. 2011

J. Toxicol. Sci.

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-The Nanoculture plate (NCP) is a recently developed plate which essentially consists of a textured surface with specific characteristics that induce spheroid formation: microfabrications with a micro-square pattern on the culture surface. The NCP can be used to generate uniform adhesive spheroids of cancer cell lines using conventional techniques without the need of any animal compounds. In this study, we assessed the performance of human hepatoma cell line HepG2 cells cultured with an NCP to evaluate the effects of the NCP on their hepatocyte-specific functions. The NCP facilitated the formation of three-dimensional (3D) HepG2 cell architecture. HepG2 cells cultured with an NCP exhibited enhanced mRNA expression levels of albumin and cytochrome P450 (CYP) enzymes compared to those cultured with a two-dimensional (2D) conventional plate. The expression levels of two specific liver-enriched transcription factors, hepatocyte nuclear factor 4α (HNF4α) and CCAAT/enhancer binding protein α (C/EBPα), were higher in HepG2 cells grown with the NCP than those in HepG2 cells grown with conventional plates before albumin and CYP enzymes expression levels were increased. The inducibility of CYP1A2 and CYP3A4 mRNA following exposure to inducers in HepG2 cells cultured with an NCP was comparable to that in HepG2 cells cultured with conventional plates, while the expression levels of CYP1A2 and CYP3A4 mRNA following exposure to inducers were higher when using an NCP than when using conventional plates. These results suggest that the use of an NCP enhances the hepatocyte-specific functions of HepG2 cells, such as drug-metabolizing enzyme expression, making the NCP/ HepG2 system a useful tool for evaluating drug metabolism in vitro.

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Sex and circadian modulatory effects on rat liver as assessed by transcriptome analyses

Cited by 29 publications

References 56 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

Data on Wistar Hannover Rats from a General Toxicity Study

Expression of albumin and cytochrome P450 enzymes in HepG2 cells cultured with a nanotechnology-based culture plate with microfabricated scaffold

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