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1.
Toxicol Ind Health ; 30(5): 432-41, 2014 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-22933553

RESUMO

The endotoxin, lipopolysaccharide (LPS), of Salmonella typhimurium was biosynthetically labeled with (3)H and (14)C incorporated into the fatty acyl chains and glucosamine residues, respectively. The radio-labeled LPS was isolated from the bacteria and then injected into Sprague-Dawley rats. The distribution of (14)C and (3)H-LPS in plasma and other organs was determined following intraperitoneal (IP) doses of (14)C and (3)H-LPS (200 µg/kg). Plasma concentrations of both fatty acyl chains and glucosamine residues were biphasic, with a relatively rapid decay followed by a slow decline for 48 h. Similar biphasic results were found in the peripheral organs (kidney and heart) and brain barrier tissues (meninges and choroid plexus). In other brain tissues (brain stem, caudate nucleus, hypothalamus, frontal cortex, cerebellum and hippocampus), the glucosamine residue was biphasic, whereas the fatty acyl chains showed accumulation. Highest concentrations of LPS were found in the plasma, spleen and the liver. In addition, in the liver, sustained elevations of (14)C-glucosamine and (3)H-fatty acyl chains were observed. This indicates LPS accumulation in the liver. By contrast, the spleen showed biphasic decay of glucosamine residues and accumulation of fatty acyl chains. In the brain barrier tissues, peak LPS concentrations were significantly reduced (about 70%) and were further reduced (about 95%) in other brain tissues. The high elevation of LPS in the spleen is considered indicative of an immune response. Our findings highlight the potential significant role of lipid A as shown with the sustained elevation of (3)H-fatty acyl chains in the brain.


Assuntos
Química Encefálica , Endotoxinas/farmacocinética , Animais , Tronco Encefálico/química , Radioisótopos de Carbono , Núcleo Caudado/química , Cerebelo/química , Plexo Corióideo/química , Endotoxinas/análise , Endotoxinas/sangue , Lobo Frontal/química , Hipocampo/química , Hipotálamo/química , Rim/química , Fígado/química , Meninges/química , Miocárdio/química , Ratos , Ratos Sprague-Dawley , Baço/química , Distribuição Tecidual , Trítio
2.
Food Chem Toxicol ; 43(4): 505-13, 2005 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-15721196

RESUMO

Thirty-day old female rats received corn oil or androstenedione (in corn oil) at one of four concentrations (5.0, 10.0, 30.0 or 60.0 mg/kg body weight) by gavage for two weeks prior to mating, during the mating period and until gestation day (GD) 19. Caesarean sections were performed on GD 20. No dose related changes were observed in serum androstenedione, estradiol, LH, FSH, testosterone or progesterone. A statistically significant decrease in estrous cycle length was observed in the 60.0 mg/kg dose group only. Feed and fluid consumption, mean body weight gain, organ weight and fetal parameters were not affected by androstenedione treatment. At the doses given, androstenedione had no specific effect on the development of individual bones or soft tissues.


Assuntos
Androstenodiona/toxicidade , Estro/efeitos dos fármacos , Desenvolvimento Fetal/efeitos dos fármacos , Troca Materno-Fetal , Administração Oral , Animais , Osso e Ossos/embriologia , Relação Dose-Resposta a Droga , Estro/fisiologia , Feminino , Masculino , Gravidez , Ratos
3.
Food Chem Toxicol ; 43(2): 341-4, 2005 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-15621347

RESUMO

Androstenedione, a naturally occurring steroid hormone, is a dietary supplement used to enhance athletic performance. Little is known, however, about the safety of its use by young adults including women of child bearing age. To test the possible hepatotoxic effects of androstenedione use, this study was undertaken using a rat model. Pregnant rats (six rats/dose) were exposed to androstenedione in corn oil by gastric intubation at 0, 5, 30 or 60 mg/kg body weight/day beginning 2 weeks before mating and continuing through gestation day 19. On gestation day 20, blood and livers were collected from the pregnant rats for analysis of hepatotoxicity endpoints: serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), lactate dehydrogenase (LDH), glutathione (GSH) and glutathione S-transferase (GST), total microsomal P450, nuclear DNA damage and lipid peroxidation. Under these experimental conditions, no significant differences were observed in any of these biomarkers over the concentration range examined.


Assuntos
Androstenodiona/toxicidade , Fígado/efeitos dos fármacos , Administração Oral , Alanina Transaminase/metabolismo , Animais , Aspartato Aminotransferases/metabolismo , Sistema Enzimático do Citocromo P-450/metabolismo , Dano ao DNA/efeitos dos fármacos , Suplementos Nutricionais , Relação Dose-Resposta a Droga , Feminino , Glutationa/metabolismo , Glutationa Transferase/metabolismo , L-Lactato Desidrogenase/metabolismo , Peroxidação de Lipídeos/efeitos dos fármacos , Fígado/enzimologia , Gravidez , Ratos , Ratos Sprague-Dawley , Segurança
4.
J Appl Toxicol ; 28(5): 703-9, 2008 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-18059068

RESUMO

Androstenedione, a naturally occurring steroid hormone, has been used to enhance athletic performance. Little is known, however, about its hepatotoxicity. Clone-9 cells, a non-transformed epithelial cell line that was originally isolated from normal liver of a 4-week old Sprague-Dawley rat, were used as an in vitro model to assess the hepatotoxic potential of androstenedione. The cultures were treated with androstenedione for 24 h at 37 degrees C in 5% CO(2) at concentrations of 0-100 microg ml(-1). After the treatment period, the cells and the culture supernatants were assayed for markers of cytotoxicity which included: release of liver enzymes, cell viability, cellular double-stranded DNA content, oxidative stress, steatosis, cellular ATP content, caspase-3 activity, the mitochondrial permeability transition and induction of cytochrome P450 activity. Significant concentration-dependent differences from control were observed in some endpoints at medium concentrations of 10 microg ml(-1) and above. These in vitro findings were compared with comparable endpoints obtained from an in vivo study of androstenedione toxicity in female Sprague-Dawley rats. Of the eight endpoints that could be compared between the two studies, only three (lipid accumulation, ATP depletion and P450 activity) appeared to be concordant. This suggests that, under the experimental conditions used, the clone-9 cells were not a good model for androstenedione hepatotoxicity.


Assuntos
Androstenodiona/toxicidade , Doença Hepática Induzida por Substâncias e Drogas/patologia , Trifosfato de Adenosina/metabolismo , Animais , Biomarcadores , Caspase 3/metabolismo , Linhagem Celular , Células Clonais , DNA/biossíntese , DNA/genética , Enzimas/sangue , Enzimas/metabolismo , Feminino , Hepatócitos/efeitos dos fármacos , Hepatócitos/enzimologia , Fígado/citologia , Fígado/efeitos dos fármacos , Fígado/patologia , Modelos Biológicos , Estresse Oxidativo/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Reprodutibilidade dos Testes
5.
J Appl Toxicol ; 24(3): 177-81, 2004.
Artigo em Inglês | MEDLINE | ID: mdl-15211610

RESUMO

The biosynthetically double-labeled lipopolysaccharide (LPS), containing (3)H-labeled on the fatty acyl-chains and (14)C-labeled on the glucosamine of Salmonella enterica serotype typhimurium, was isolated from bacteria grown in proteose peptone-beef extract (PPBE) medium in the presence of labeled precursors; 133 micro Ci/ml of [2-(3)H] acetate sodium salt and 0.167 micro Ci/ml of N-acetyl[D-1-(14)C]glucosamine. The LPS was extracted from the bacteria with 90% phenol/chloroform/petroleum ether, purified and stored in 0.1% (v/v) triethylamine/10 mM Tris HCl at -70 degrees C. Tissue slices and portions of the meninges were prepared and incubated in artificial cerebrospinal fluid (CSF) or Krebs phosphate buffer (Krebs) containing 150 ng/ml LPS with [(3)H] LPS (0.004 micro Ci/ml, sp. act. 28 micro Ci/mg LPS). The tissues were incubated under 95% oxygen/5% carbon dioxide at 37 degrees C with constant agitation until steady-state uptake was reached (60 min). At the end of the incubation period, tissues were processed for radioactivity measurement. The rat tissue partitioning of LPS in artificial CSF for brain and Krebs for other organs was measured by using the ratio of tissue to medium at the steady state in vitro. The following results were obtained from the study: Heart, 0.15; liver, 0.19; spleen, 0.12; kidney, 0.18; stomach, 0.17; small intestine, 0.18; brain stem, 0.10; cerebellum, 0.11; meninges, 0.77; hippocampus, 0.12; hypothalamus, 0.12; frontal cortex, 0.09 and caudate nucleus, 0.10. This information, along with plasma or blood/buffer partition coefficients, is a requisite for constructing a physiologically-based pharmacokinetic (PBPK) model of endotoxins for quantitative risk assessment.


Assuntos
Endotoxinas/farmacocinética , Lipopolissacarídeos/isolamento & purificação , Salmonella typhimurium , Distribuição Tecidual , Animais , Modelos Biológicos , Ratos , Ratos Sprague-Dawley
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