scholarly journals Novel Gender-Related Regulation of CYP2C12 Gene Expression in Rats

2005 ◽  
Vol 19 (5) ◽  
pp. 1181-1190 ◽  
Author(s):  
Megumi Endo ◽  
Yoshiki Takahashi ◽  
Yasumasa Sasaki ◽  
Tetsuya Saito ◽  
Tetsuya Kamataki
Keyword(s):  
Histone Deacetylase ◽  
Chromatin Structure ◽  
Female Rats ◽  
Male Rats ◽  
Male Rat ◽  
Female Rat ◽  
Hypersensitive Site ◽  
Responsive Element ◽  
Male Specific ◽  
Rat Livers

Abstract The expression of CYP2C12 by GH occurs in female but not in male rat livers. Direct injection of the CYP2C12 promoter-luciferase gene into male rat livers showed that the CYP2C12 promoter was active in both male and female rats. Thus, to further examine one or more factors that regulate the gender-related expression of CYP2C12, male rats were treated with trichostatin A, a specific inhibitor of histone deacetylase capable of condensing the chromatin structure. Interestingly, the expression of CYP2C12 by GH was seen even in the livers of male rats, indicating that histone deacetylase contributes to the suppression of CYP2C12 expression in male rats. Deoxyribonuclease I hypersensitive assay using nuclei from the livers of male or female rats revealed that the chromatin structure of the CYP2C12 gene was gender specific: a hypersensitive site at a position −4.2 kb containing GH-responsive element that bound to signal transducer and activator of transcription 5 (STAT5), termed as HS (hypersensitive site) 1, was specific for female rat livers, whereas a hypersensitive site at a position −3 kb, designated as HSm (male-specific hypersensitive site), was characteristic of male rat livers. A −3425/−3275 region within HSm functioned as a negative regulatory region, when the region was inserted in front of simian virus 40 promoter. Gel shift assay demonstrated that both CCAAT/enhancer-binding protein α and β bound to the −3425/−3275 region. Based on these results, we conclude that the gender-related expression of the CYP2C12 gene results from the inaccessibility of to STAT5 to the GH-responsive element by chromatin condensation seen in male rat livers, and from the presence of the male-specific HSm that acts as a silencer.

scholarly journals Sex differences in the hydroxylation of cholecalciferol and of 5 β-cholestane-3 α, 7 α, 12 α-triol in rat liver

1987 ◽  
Vol 247 (1) ◽  
pp. 73-78 ◽  
Author(s):  
K Saarem ◽  
J I Pedersen
Keyword(s):  
Sex Hormones ◽  
Rat Liver ◽  
Female Rats ◽  
Regulatory Control ◽  
Male Rats ◽  
Male Rat ◽  
Female Rat ◽  
Significant Difference ◽  
Alpha 7 ◽  
Rat Livers

The effect of sex hormones on hydroxylation of cholecalciferol (‘vitamin D3’) and of 5 beta-cholestane-3 alpha, 7 alpha, 12 alpha-triol has been investigated in female- and male-rat livers. The mitochondrial cholecalciferol 25-hydroxylase and C27-steroid 27-hydroxylase activities were respectively 4.6- and 2.7-fold higher in female- than in male-rat livers. The microsomal 1 alpha-hydroxycholecalciferol 25-hydroxylase was 2.8-fold higher in male- than in female-rat liver. No significant difference was found in the microsomal 25-hydroxylation of 5 beta-cholestane-3 alpha, 7 alpha, 12 alpha-triol. Liver microsomes (microsomal fractions) from male, but not from female, rats also catalysed 1-hydroxylation of 5 beta-cholestane-3 alpha, 7 alpha, 12 alpha-triol. Injection of testosterone into female rats decreased the mitochondrial cholecalciferol 25-hydroxylase and C27-steroid 27-hydroxylase activities, but not to a statistically significant extent. Testosterone treatment had no effect on the microsomal hydroxylases in female-rat liver. Injection of oestradiol valerate to male rats resulted in increased activities of both mitochondrial hydroxylases to the same levels as those of control females, while the microsomal enzyme activities decreased. The present results indicate that sex hormones exert a regulatory control on the mitochondrial cholecalciferol 25-hydroxylase and C27-steroid 27-hydroxylase activities.

scholarly journals Increased bioactivation of dihaloalkanes in rat liver due to induction of class Theta glutathione S-transferase T1-1

1998 ◽  
Vol 335 (3) ◽  
pp. 619-630 ◽  
Author(s):  
Philip J. SHERRATT ◽  
Margaret M. MANSON ◽  
Anne M. THOMSON ◽  
Erna A. M. HISSINK ◽  
Gordon E. NEAL ◽  
...  
Keyword(s):  
Western Blotting ◽  
Rat Liver ◽  
Female Rats ◽  
Male Rats ◽  
Male Rat ◽  
Female Rat ◽  
Glutathione S Transferase ◽  
Chemopreventive Agents ◽  
Cytoplasmic Staining ◽  
Potent Inducer

A characteristic feature of the class Theta glutathione S-transferase (GST) T1-1 is its ability to activate dichloromethane and dibromoethane by catalysing the formation of mutagenic conjugates. The level of the GSTT1 subunit within tissues is an important determinant of susceptibility to the carcinogenic effects of these dihaloalkanes. In the present study it is demonstrated that hepatic GST activity towards these compounds can be elevated significantly in female and male Fischer-344 rats by feeding these animals on diets supplemented with cancer chemopreventive agents. Immunoblotting experiments showed that increased activity towards the dihaloalkanes is associated with elevated levels of the GSTT1 subunit in rat liver. Sex-specific effects were observed in the induction of GSTT1 protein. Amongst the chemopreventive agents tested, indole-3-carbinol proved to be the most potent inducer of hepatic GSTT1 in male rats (6.2-fold), whereas coumarin was the most potent inducer of this subunit in the livers of female rats (3.5-fold). Phenobarbital showed significant induction of GSTT1 only in male rat liver and had little effect in female rat liver. Western blotting showed that class Alpha, Mu and Pi GST subunits are not co-ordinately induced with GSTT1, indicating that the expression of GSTT1 is determined, at least in part, by mechanisms distinct from those that regulate levels of other transferases. The increase in amount of hepatic GSTT1 protein was also reflected by an increase in the steady-state level of mRNA in response to treatment with chemopreventive agents and model inducers. Immunohistochemical detection of GSTT1 in rat liver supported the Western blotting data, but showed, in addition to cytoplasmic staining, significant nuclear localization of the enzyme in hepatocytes from some treated animals, including those fed on an oltipraz-containing diet. Significantly, the hepatic level of cytochrome P-450 2E1, an enzyme which offers a detoxification pathway for dihaloalkanes, was unchanged by the various inducing agents studied. It is concluded that the induction of GSTT1 by dietary components and its localization within cells are important factors that should be considered when assessing the risk dihaloalkanes pose to human health.

Effects of acute administration of 2-hydroxylated metabolites of oestrogens on LH and prolactin secretion in male and female prepubertal rats

1984 ◽  
Vol 103 (3) ◽  
pp. 317-325
Author(s):  
A. K. Brar ◽  
G. Fink
Keyword(s):  
Plasma Concentration ◽  
Female Rats ◽  
Male Rats ◽  
Male Rat ◽  
Female Rat ◽  
Uterine Weight ◽  
Immature Female ◽  
Male And Female ◽  
Immature Male ◽  
Lh Release

ABSTRACT The effects of catechol oestradiol and catechol oestrone on the release of LH and prolactin were investigated in immature male and female Wistar rats. In male rats both catechol oestradiol and catechol oestrone significantly increased the plasma concentration of LH, and catechol oestradiol but not catechol oestrone significantly increased the plasma concentration of prolactin and decreased the pituitary concentration of LH. The parent oestrogens, oestradiol-17β and oestrone, had no effect on plasma LH concentrations, but both increased significantly the plasma concentration of prolactin, and oestrone but not oestradiol-17β increased the pituitary concentration of LH. In immature female rats, catechol oestradiol inhibited the surge of LH and the increase in uterine weight induced by injecting pregnant mare serum gonadotrophin (PMSG). The injection of oestrone induced an increase in the plasma concentration of LH which was about nine times greater than that produced by oestradiol-17β. There were no significant differences in the effects of these steroids on plasma prolactin concentration. These results (i) confirm that in the immature male rat catechol oestrogens can stimulate LH release and show that catechol oestradiol can increase prolactin release, (ii) show that catechol oestradiol can inhibit the stimulatory effects of PMSG on LH release and uterine weight in the immature female rat, and (iii) demonstrate that oestrone can stimulate LH release in the immature female rat. J. Endocr. (1984) 103, 317-325

scholarly journals Sex-Related Liver Injury Due to Alcohol Involves Activation of Kupffer Cells by Endotoxin

2000 ◽  
Vol 14 (suppl d) ◽  
pp. 129D-135D ◽  
Author(s):  
Ronald G Thurman
Keyword(s):  
Liver Injury ◽  
Kupffer Cells ◽  
Coupling Constants ◽  
Female Rats ◽  
Male Rat ◽  
Gadolinium Chloride ◽  
Female Rat ◽  
Ethanol Treatment ◽  
Necrosis Factor Alpha ◽  
Rat Livers

Females have a greater susceptibility to ethanol-induced liver injury than males. Females who drink ethanol regularly and have been overweight for 10 years or more are at greater risk for both hepatitis and cirrhosis than males, and females develop ethanol-induced liver injury more rapidly and with less ethanol than males. Female rats on an enteral ethanol protocol exhibit injury more quickly than males and have widespread fatty changes over a larger portion of the liver lobule. Moreover, levels of plasma endotoxin, intracellular adhesion molecule-1, free radical adducts, infiltrating neutrophils and nuclear factor kappa B are doubled in female rat livers compared with male rat livers after enteral ethanol treatment. Additionally, estrogen treatment in vivo increases the sensitivity of hepatic macrophages or Kupffer cells to endotoxin. Evidence has been presented that Kupffer cells are pivotal in the development of ethanol-induced liver injury. Destroying Kupffer cells with gadolinium chloride or decreasing bacterial endotoxin by sterilizing the gut with antibiotics inhibits early inflammation due to ethanol. Similar results have been obtained with anti-tumour necrosis factor-alpha antibody. These data pointed to the hypothesis that ethanol-induced liver injury involves elevations in circulating endotoxin concentrations leading to activation of Kupffer cells, which causes a hypoxia-reoxygenation injury. This theory has been tested using pimonidazole, a 2-nitroimidazole marker, to quantify hypoxia in downstream, pericentral regions of the hepatic lobule. After chronic enteral ethanol treatment, pimonidazole binding doubles. Enteral ethanol also increases free radicals detected with electron spin resonance. Radical adducts, with coupling constants such as alpha-hydroxyethyl radical, have been shown to arise from ethanol. Importantly, hypoxia and radical production detected in bile are also decreased by the destruction of Kupffer cells with gadolinium chloride. These data support the hypothesis that Kupffer cells contribute to the vital sex differences in liver injury caused by ethanol.

EXPERIMENTAL EVALUATION OF DIURETICS IN THE RAT

1956 ◽  
Vol 34 (1) ◽  
pp. 903-911
Author(s):  
J. D. McColl ◽  
J. M. Parker ◽  
J. K.W. Ferguson
Keyword(s):  
Carbonic Anhydrase ◽  
Dose Range ◽  
Carbonic Anhydrase Inhibitor ◽  
Female Rats ◽  
Male Rats ◽  
Male Rat ◽  
High Dose ◽  
Female Rat ◽  
Inhibitor Type ◽  
Almost All

The diuretic response of the male and the female rat to aminophylline has been studied when these animals were pretreated with various concentrations of sodium chloride solution. A linear log dose – response curve was obtained over the dose range employed with male rats pretreated with 0.45% and 2% saline. Male rats exhibited a diuresis with 4% saline which was not increased by aminophylline. Female rats showed diuresis but the responses were more variable for almost all combinations of electrolyte load and xanthine dose. When they were pretreated with 0.45% and 2% saline, aminophylline caused some additional production of urine but this was much less regular than that observed with males. The variation in response to aminophylline after 4% saline was very marked but the trend suggested that the xanthine had a diuretic effect at the high dose. The diuretic responses to a xanthine, a mercurial, and a carbonic anhydrase inhibitor type of diuretic were compared in the male rat. Peak responses were smallest after the mercurial diuretic and greatest with the carbonic anhydrase inhibitor.

scholarly journals Mode of GH administration and gene expression in the female rat brain

2017 ◽  
Vol 233 (2) ◽  
pp. 187-196 ◽  
Author(s):  
Marion Walser ◽  
Linus Schiöler ◽  
Jan Oscarsson ◽  
Maria A I Åberg ◽  
Ruth Wickelgren ◽  
...  
Keyword(s):  
Mixed Model ◽  
Brain Regions ◽  
Female Rats ◽  
Male Rats ◽  
Male Rat ◽  
Sexually Dimorphic ◽  
Female Rat ◽  
Expression Levels ◽  
Mixed Model Analysis ◽  
Significant Difference

The endogenous secretion of growth hormone (GH) is sexually dimorphic in rats with females having a more even and males a more pulsatile secretion and low trough levels. The mode of GH administration, mimicking the sexually dimorphic secretion, has different systemic effects. In the brains of male rats, we have previously found that the mode of GH administration differently affects neuron–haemoglobin beta (Hbb) expression whereas effects on other transcripts were moderate. The different modes of GH administration could have different effects on brain transcripts in female rats. Hypophysectomised female rats were given GH either as injections twice daily or as continuous infusion and GH-responsive transcripts were assessed by quantitative reverse transcription polymerase chain reaction in the hippocampus and parietal cortex (cortex). The different modes of GH-administration markedly increased Hbb and 5′-aminolevulinate synthase 2 (Alas2) in both brain regions. As other effects were relatively moderate, a mixed model analysis (MMA) was used to investigate general effects of the treatments. In the hippocampus, MMA showed that GH-infusion suppressed glia- and neuron-related transcript expression levels, whereas GH-injections increased expression levels. In the cortex, GH-infusion instead increased neuron-related transcripts, whereas GH-injections had no significant effect. Interestingly, this contrasts to previous results obtained from male rat cortex where GH-infusion generally decreased expression levels. In conclusion, the results indicate that there is a small but significant difference in response to mode of GH administration in the hippocampus as compared to the cortex. For both modes of GH administration, there was a robust effect on Hbb and Alas2.

scholarly journals Benoxacor Is Enantioselectively Metabolized By Rat Liver Subcellular Fractions

2020 ◽  
Author(s):  
Derek Simonsen ◽  
David M. Cwiertny ◽  
Hans-Joachim Lehmler
Keyword(s):  
Environmental Fate ◽  
Female Rats ◽  
Male Rats ◽  
Male Rat ◽  
Cytochrome P450 Enzymes ◽  
Transport Studies ◽  
Glutathione S Transferases ◽  
Mammalian Toxicity ◽  
Rat Livers

This study investigated the enantioselective metabolism of benoxacor, an ingredient of herbicide formulations, in rats in vitro. Benoxacor was incubated for ≤ 30 minutes with microsomes or cytosol from female or male rat livers, and its enantioselective depletion was measured using gas chromatographic methods. Benoxacor was depleted in incubations with active microsomes, suggesting its metabolism by hepatic cytochrome P450 enzymes. In the presence of glutathione, benoxacor was also depleted in cytosolic incubations, consistent with its metabolism by glutathione S-transferases. The depletion of benoxacor was faster in incubations with cytosols from male than female rats, whereas no statistically significant sex-differences was observed in microsomal incubations. Microsomal incubations showed an enrichment of the first eluting benoxacor enantiomer (E<sub>1</sub>-benoxacor). A greater enrichment occurred in incubations with microsomes from female (EF=0.67±0.01) than male rats (EF=0.60±0.01). Cytosolic incubations from female rats resulted in enrichment of E<sub>1</sub>-benoxacor (EF=0.54±0.01), while cytosolic incubations from male rats displayed enrichment of the second eluting enantiomer (E<sub>2</sub>-benoxacor; EF=0.43±0.01). Sex-dependent differences in the metabolism of benoxacor in rats could significantly impact ecological risks and mammalian toxicity. Our results also suggest changes in the enantiomeric enrichment of benoxacor may be a powerful tool for source apportionment and environmental fate and transport studies. <br>

EXPERIMENTAL EVALUATION OF DIURETICS IN THE RAT

1956 ◽  
Vol 34 (5) ◽  
pp. 903-911 ◽  
Author(s):  
J. D. McColl ◽  
J. M. Parker ◽  
J. K.W. Ferguson
Keyword(s):  
Carbonic Anhydrase ◽  
Dose Range ◽  
Carbonic Anhydrase Inhibitor ◽  
Female Rats ◽  
Male Rats ◽  
Male Rat ◽  
High Dose ◽  
Female Rat ◽  
Inhibitor Type ◽  
Almost All

The diuretic response of the male and the female rat to aminophylline has been studied when these animals were pretreated with various concentrations of sodium chloride solution. A linear log dose – response curve was obtained over the dose range employed with male rats pretreated with 0.45% and 2% saline. Male rats exhibited a diuresis with 4% saline which was not increased by aminophylline. Female rats showed diuresis but the responses were more variable for almost all combinations of electrolyte load and xanthine dose. When they were pretreated with 0.45% and 2% saline, aminophylline caused some additional production of urine but this was much less regular than that observed with males. The variation in response to aminophylline after 4% saline was very marked but the trend suggested that the xanthine had a diuretic effect at the high dose. The diuretic responses to a xanthine, a mercurial, and a carbonic anhydrase inhibitor type of diuretic were compared in the male rat. Peak responses were smallest after the mercurial diuretic and greatest with the carbonic anhydrase inhibitor.

Induction of prolactin receptors in the liver is more closely related to the growth-promoting than to the lactogenic potency of peptides

1987 ◽  
Vol 114 (3) ◽  
pp. 350-356 ◽  
Author(s):  
G. Norstedt ◽  
B. Husman ◽  
A. Mode ◽  
P. Eneroth ◽  
U.J. Lewis ◽  
...  
Keyword(s):  
Time Course ◽  
Mature Female ◽  
Female Rats ◽  
Male Rats ◽  
Female Rat ◽  
Hypophysectomized Rats ◽  
Liver Membranes ◽  
Growth Promoting ◽  
Rat Livers

Abstract. The sex differentiated binding 125I-human prolactin (PRL) to rat liver membranes was studied and the present results extend our previous studies on induction of hepatic PRL receptors by growth hormone (GH). In prepubertal female rats, PRL receptor levels are low compared with those in mature female rat livers. Infusion of hGH during one week to 17-day-old female rats resulted in a receptor level typical of adult female rats. The time course of receptor disappearance in male rats treated with hGH was also studied. When the receptor-inducing hormone was removed, receptor levels in hGH-treated male rats returned to the normal level characteristic of male rats after approximately 96 h. The specificity of various GH-like and PRL-like hormones in PRL receptor induction was studied in hypophysectomized rats. The PRL-like hormones were identified by measuring their potency to displace 125I-hPRL from a receptor preparation obtained from female rat livers, and the GH-like hormones were identified by their potency to increase body weight in hypophysectomized rats. Using similar doses of hormones it was found that in vivo administration of growth-promoting peptides (rGH, hGH, bGH) induced PRL receptors, whereas lactogenic hormones (rPRL, hPL) had a very small or no effect on PRL receptor induction. This suggests that binding to a type of GH receptor is the first step in PRL receptor induction.

Subacute co-exposure to low doses of ruthenium(III) changes the distribution, excretion and biological effects of silver ions in rats

2020 ◽  
Vol 17 (2) ◽  
pp. 163 ◽  
Author(s):  
Nicoleta Vedeanu ◽  
Cezara Voica ◽  
Dana Alina Magdas ◽  
Bela Kiss ◽  
Maria-Georgia Stefan ◽  
...  
Keyword(s):  
Biological Effects ◽  
Female Rats ◽  
Male Rats ◽  
Male Rat ◽  
Human Organism ◽  
Critical Element ◽  
Female Rat ◽  
Low Doses ◽  
Subacute Toxicity ◽  
Liver And Kidney

Environmental contextAlthough ruthenium is a technology-critical element used in several new industries, little is known about its environmental impact or possible human health risks. We report a toxicological evaluation of laboratory animals during co-exposure to ruthenium and silver. We identified interactions between the two elements that could lead to unwanted biological effects. AbstractRuthenium is one of the rarest metals on Earth that is classified as a technology-critical element (TCE). Silver, however, is well known for its antibacterial and immunostimulant properties. The increasing use of Ru and Ag in medicine and daily life makes simultaneous exposure possible, with unknown pharmacokinetic or toxicological consequences for the human organism. Thus, the present study investigated the influence of co-exposure to RuIII on the subacute toxicity of Ag ions in rats after repeated daily administration for 28 days of low doses by oral gavage. The subacute toxicity was investigated by the evaluation of several biochemical and hematological parameters, evaluation of specific oxidative stress biomarkers from liver and kidney, and histopathological investigation of liver and kidney tissue samples after 28 days of exposure in female rats. In addition, Ag and Ru concentrations were determined by inductively coupled plasma mass spectrometry (ICP-MS) in urine, liver and kidney parenchyma in male rats. The obtained results showed that co-exposure to low doses of RuIII and Ag did not produce any significant biochemical, hematological or histopathological alterations in the treated female rat groups, except for an increased red cell distribution width (RDW) value. A decrease of urinary excretion of Ag and of the Ag concentration in kidneys was observed in the male rat group co-exposed to RuIII and Ag. This is the first invivo study investigating the toxic effect of co-exposure to low doses of Ag and Ru ions, and the obtained results may justify further research on this subject, mainly on the investigation of possible competitive mechanisms.

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