المؤلفون: A. Jay Gandolfi, Jayanthika B. Wijeweera, T. Alan Parrish, R. Clark Lantz

المصدر: Toxicological Sciences. 61:283-294

مصطلحات موضوعية: Male, Time Factors, Sodium arsenite, Arsenites, Cell Survival, Blotting, Western, Fluorescent Antibody Technique, In Vitro Techniques, Biology, Toxicology, Rats, Sprague-Dawley, chemistry.chemical_compound, Genes, jun, Heat shock protein, Macrophages, Alveolar, Gene expression, Animals, Lung, Transcription factor, Heat-Shock Proteins, Arsenite, Microscopy, Confocal, NF-kappa B, Sodium Compounds, Molecular biology, In vitro, Rats, DNA-Binding Proteins, Transcription Factor AP-1, Gene Expression Regulation, chemistry, Biochemistry, Potassium, Signal transduction, Immediate early gene, Signal Transduction

الوصف: Arsenic is a known human carcinogen. These studies were designed to examine the impact of low arsenite concentrations on immediate early gene expression in precision-cut rat lung slices. Precision-cut lung slices are a versatile in-vitro system for toxicity studies, as they preserve the architecture and cellular heterogeneity of the lung. Since 0.1-100 microM arsenite did not compromise slice viability at 4 hours, effects of arsenite on the expression of c-jun/AP-1, NFkappaB, HSP 32, HSP 72, HSP 60, and HSP 90 were studied, using these concentrations of arsenite at 4 h. Nuclear c-jun was increased by 10 and 100 microM arsenite, while NFkappaB was not affected. Gel-shift assays indicated that 10 microM arsenite resulted in an enhanced DNA-binding activity of both AP-1 and NFkappaB. Confocal microscopic analysis of AP-1 indicated nuclear localization of this transcription factor, mainly in type-II epithelial cells and alveolar macrophages. Nuclear localization of NFkappaB was lower than that observed for AP-1, while most of the NFkappaB was localized to cytoplasm of type-II epithelial cells and alveolar macrophages. HSP 32 was increased by 1.0 and 10 microM arsenite, while HSP 72 was increased by only 100 microM arsenite. HSP 60 and HSP 90 were not changed by arsenite. These studies indicate that noncytotoxic concentrations of arsenite are capable of affecting signal transduction pathways and gene expression in the lung.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::7101bc2b18be7a1ed0a1f6a3e3dbb562Test
https://doi.org/10.1093/toxsci/61.2.283Test

المؤلفون: R. C. Lind, A. Jay Gandolfi

المصدر: Toxicologic Pathology. 27:342-347

مصطلحات موضوعية: Male, medicine.medical_specialty, Time Factors, medicine.medical_treatment, Pharmacology, Toxicology, 030226 pharmacology & pharmacy, Pathology and Forensic Medicine, Rats, Sprague-Dawley, Lesion, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Image Processing, Computer-Assisted, medicine, Animals, Dimethyl Sulfoxide, Antidote, Molecular Biology, Liver injury, Dimethyl sulfoxide, Alanine Transaminase, Cell Biology, medicine.disease, Rats, Surgery, Liver, chemistry, Hepatoprotection, Bromobenzene, 030220 oncology & carcinogenesis, Acute Disease, Toxicity, Chloroform, Chemical and Drug Induced Liver Injury, medicine.symptom, Bromobenzenes, Toxicant

الوصف: Dimethyl sulfoxide (DMSO) has previously been reported to protect against hepatotoxicity resulting from chloroform (CHCl3) or bromobenzene (BB) when given 10 hr after the toxicant. The object of these studies was to further demonstrate the latent protective ability of DMSO by administering it at a much later time (24 hr) following toxicant exposure. In addition, a more detailed evaluation of the lesions was performed to better characterize the lesion progression and resolution. Male Sprague-Dawley rats received a hepatotoxic oral dose of either CHCl3 (1.0 ml/kg) or BB (0.5 ml/kg) and then received 2 ml/kg DMSO intraperitoneally 24 hr later. With both toxicants, limited centrilobular lesions were already present by the time DMSO was administered. Without treatment, liver injury rapidly progressed so that by 48 hr it occupied 40-50% of the liver, with accompanying large increases in plasma alanine aminotransferase (ALT) activity. Administration of DMSO greatly attenuated lesion development for both toxicants; the area injured was reduced by more than 4-fold, accompanied by a decrease in 48 hr ALT activity of 8-16-fold. The ability of DMSO to intervene in the development of liver injury at such a late time appears to be unique and may provide insight into therapies for acute xenobioticinduced hepatitis.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::26a1edfdf65c497744eb6dcbbb094924Test
https://doi.org/10.1177/019262339902700310Test

المؤلفون: Klaus Brendel, Lynnda L. Reid, A. Jay Gandolfi, Heriberto P. Mata, Shana Azri

المصدر: Toxicology and Applied Pharmacology. 112:81-86

مصطلحات موضوعية: Male, medicine.medical_specialty, Time Factors, Sorbitol dehydrogenase, Tetrazolium Salts, CCL4, Dehydrogenase, Biology, Toxicology, Lipid peroxidation, chemistry.chemical_compound, Cytochrome P-450 Enzyme System, Internal medicine, Lactate dehydrogenase, medicine, Animals, Carbon Tetrachloride, Pharmacology, Rats, Inbred Strains, Fasting, Rats, Kinetics, Thiazoles, Endocrinology, Liver, chemistry, Biochemistry, Toxicity, Carbon tetrachloride, Phenobarbital, Lipid Peroxidation, medicine.drug

الوصف: Lipid peroxidation and loss of enzymes located predominantly in either periportal or centrilobular hepatocytes were investigated in precision-cut liver slices from male Sprague-Dawley rats. Pretreatment of animals with 80 mg/kg phenobarbital for the site-specific enzyme studies enhanced and accelerated CCl 4 toxicity in slices resulting from increased radical formation. Liver slices were exposed to 0.57 m m CCl 4 by vaporization using a roller incubation system at 37°C for a total of 9 hr. Conjugated diene formation, an index of lipid peroxidation, was detected 15 min following CCl 4 administration and increased over time. Loss of cytochrome P450 occurred in a time-dependent manner relative to controls where levels in treated slices were 42% of controls at 9 hr. A 48-hr fast prior to termination increased intracellular K + leakage relative to that present in slices from fed animals. Significant leakage of glucose-6-phosphate dehydrogenase and β-glucuronidase from centrilobular hepatocytes occurred 9 hr following CCl 4 administration. The content of the periportal enzymes (lactate dehydrogenase and sorbitol dehydrogenase) was unchanged in the same slices over the duration of the experiment. Reduction of 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide, a mitochondrial selective dye and indicator of viability, was significantly lower in treated slices from phenobarbital-treated animals at 9 hr relative to controls. These studies demonstrate that precision-cut slices are an ideal in vitro system for mechanistic studies and the investigation of site-specific toxicants since the integral architecture of the liver and cellular identity are maintained.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::008e6138a225141032ef1dd00a1fac48Test
https://doi.org/10.1016/0041-008xTest(92)90282-w

المؤلفون: Heriberto P. Mata, Shana Azri-Meehan, A. Jay Gandolfi, Klaus Brendel

المصدر: Toxicology. 73:239-250

مصطلحات موضوعية: Male, medicine.medical_specialty, Cell Survival, Dehydrogenase, Glucosephosphate Dehydrogenase, Biology, Toxicology, chemistry.chemical_compound, Internal medicine, Lactate dehydrogenase, medicine, Animals, Glucuronidase, chemistry.chemical_classification, Chloroform, Rats, Inbred Strains, Glutathione, Rats, Enzyme, Endocrinology, Liver, chemistry, Biochemistry, Toxicity, Potassium, Phenobarbital, Histopathology, medicine.drug

الوصف: Chloroform hepatotoxicity was investigated in precision-cut liver slices from male Sprague-Dawley rats pretreated with phenobarbital to predispose animals to CHCl 3 intoxication. Liver slices were exposed to 0.2, 0.5 and 1.0 mM chloroform for a total of 9 h in a roller culture system. Intracellular K + loss was found to be concentration- and time-dependent over the duration of the experiment. Histophathological changes were also evident. Glucose 6-phosphate dehydrogenase and β-glucuronidase were significantly decreased at 3 h relative to controls where a loss of 61% and 36% occurred, respectively. Enzyme levels of alanine aminotransferase and lactate dehydrogenase, both found predominantly in periportal hepatocytes, remained identical to controls over the duration of the experiment. A significant time-dependent depletion of glutathione occurred as early as 3 h following the administration of 0.5 mM chloroform. Mitochondrial viability, measured by the reduction of a specific dye, was significantly lower than controls in treated slices at 6 h following chloroform administration. Precision-cut liver slices appear to be especially useful for the biochemical and histopathological examination of site-specific hepatotoxicants such as CHCl 3 .

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::b2af95135407237b243cde367d9663e2Test
https://doi.org/10.1016/0300-483xTest(92)90066-n

المؤلفون: Carlos L. Krumdieck, David Rankin, Suzanne Connors, A. Jay Gandolfi, Lawrence J. Koep, Klaus Brendel

المصدر: Toxicology. 61:171-183

مصطلحات موضوعية: Adult, Male, Pathology, medicine.medical_specialty, Adolescent, Swine, Biology, Pharmacology, Toxicology, Mice, New Zealand white rabbit, Cocaine, Species Specificity, Inbred strain, In vivo, Culture Techniques, medicine, Animals, Humans, Aged, Calcium metabolism, Mice, Inbred ICR, Rats, Inbred Strains, Middle Aged, biology.organism_classification, In vitro, Rats, Liver, Mice, Inbred DBA, Cell culture, Toxicity, Potassium, Calcium, Female, Phenobarbital, Rabbits, medicine.drug

الوصف: Studies were carried out in order to find a sensitive in vitro model with which to investigate cocaine-mediated hepatotoxicity. Precision-cut liver slices were prepared from: human, domestic pig, New Zealand white rabbit, Sprague-Dawley (S/D) rat, and two mouse strains (DBA/2Ha and ICR). The rationale for the choice of these species was that information on in vivo effects of cocaine was available in the literature. Slices were cultured for up to 6 h in the presence of 0-5 mM cocaine. Indices of toxicity consisted of K+ retention and Ca2+ uptake. Minimal effects and no clear dose-response relationships were observed. In addition to the studies with non-pretreated animals, liver slices were prepared from DBA/2Ha and ICR mice, both induced by housing on pine shavings, and phenobarbital pretreated Sprague-Dawley rats. The induced ICR mouse and rat were approximately 3 times more sensitive to cocaine-mediated hepatotoxicity. The following order of sensitivity to cocaine-mediated hepatotoxicity was established: induced rat = induced ICR mouse much greater than induced DBA/2Ha mouse = rabbit = uninduced ICR mouse = uninduced DBA/2Ha mouse = uninduced rat greater than pig = human.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::7912ca76906137072c8a1abfcf9fe0e7Test
https://doi.org/10.1016/0300-483xTest(90)90018-c

المؤلفون: A. Jay Gandolfi, Carmen K. Begay

المصدر: Toxicology. 185(1-2)

مصطلحات موضوعية: Male, medicine.medical_specialty, Necrosis, Indomethacin, Toxicology, Rats, Sprague-Dawley, chemistry.chemical_compound, Indometacin, Internal medicine, medicine, Animals, Cyclooxygenase Inhibitors, Hepatoprotective Agent, Nitrobenzenes, Liver injury, Sulfonamides, biology, business.industry, Alanine Transaminase, medicine.disease, Cytoprotection, Rats, Disease Models, Animal, Endocrinology, chemistry, Alanine transaminase, biology.protein, Hepatocytes, Cyclooxygenase, Chloroform, medicine.symptom, Chemical and Drug Induced Liver Injury, business, medicine.drug, Toxicant

الوصف: Our previous studies have described the protective effects of hepatoprotective agents against liver injury elicited by chloroform even when given 24 h after the toxicant, at a time when the liver injury is taking place and rapidly developing. However, the mechanisms involved in this protection remain unknown. The cytoprotective mechanism of these hepatoprotectants such as DMSO, may be due to a dramatic shift in the production of prostaglandins that are responsible for controlling the degree of inflammatory response that can affect blood flow in the liver. In this study, NS-398, a specific COX-2 inhibitor, and indomethacin, a COX-1 and COX-2 inhibitor, were administered 24 h after chloroform dosing to determine their effect on liver injury in Sprague-Dawley rats. The extent of necrosis was evaluated by H&E staining, while injury to hepatocytes was evaluated by measuring plasma levels of alanine transaminase (ALT). Both COX inhibitors, indomethacin and NS-398, prevented an increase in (ALT) at 48 h after initial toxicant insult and attenuated further liver necrosis. No changes in cellular proliferative activity occurred in all the treatment groups, which indicates that protection from the Cyclooxygenase (COX) inhibitors did not have an effect on regeneration of cells at 32 and 48 h. These results indicate COX inhibitors provide a significant protective effect on liver cells against CHCl(3) injury and may provide further insight into therapeutic interventions against hepatotoxicants.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::e1c479072dbcf48e8b7f463b6360ae02Test
https://pubmed.ncbi.nlm.nih.gov/12505447Test

المؤلفون: Alan R. Parrish, Jeffrey M. Catania, A. Jay Gandolfi

المصدر: Drug and chemical toxicology. 24(4)

مصطلحات موضوعية: Male, Methyl Ethers, medicine.medical_specialty, Kidney Cortex, Hydrocarbons, Fluorinated, Cell Survival, Health, Toxicology and Mutagenesis, Renal cortex, In Vitro Techniques, Toxicology, Sevoflurane, In vivo, Internal medicine, medicine, Animals, Pharmacology, Kidney, Chemical Health and Safety, Chemistry, Public Health, Environmental and Occupational Health, General Medicine, Glutathione, In vitro, Rats, Inbred F344, Rats, medicine.anatomical_structure, Endocrinology, Liver, Anesthetic, Toxicity, Anesthetics, Inhalation, Degradation (geology), medicine.drug, Ethers

الوصف: Compound A (2-fluoromethoxy-1,1,3,3,3-pentafluoro-1-propene) is a degradation product of the anesthetic sevoflurane which is created in closed-circuit anesthetic machines. Past in vivo and in vitro studies have implied that Compound A is nephrotoxic via bioactivation through the cysteine conjugate beta-lyase pathway. Although glutathione (GSH) conjugates of Compound A have been reported, it is not clear if they are formed enzymatically or via direct reaction with GSH. To determine if these metabolites are produced and toxic, a tissue slice system that first exposes male Fischer 344 rat liver slices to volatilized Compound A followed by exposure of rat kidney slices to the liver incubate was employed. Liver slices exposed to volatilized Compound A (6-12 microM medium conc.; approximately 23 ppm) exhibited a loss of K+ by 6 h, which was not seen in kidney slices exposed to Compound A. Aminobenzotriazole, a cytochrome P 450 suicide inhibitor, initially inhibits the cytotoxicity of Compound A to liver slices (at these times and concentrations). The sequential liver/kidney slice experiments using Compound A have not demonstrated nephrotoxic results. GSH conjugates were synthesized and was found to be nephrotoxic at concentrations above 91 microM (18 h), with higher concentrations showing toxicity at earlier times. Additionally, non-enzymatic reactions of Compound A with GSH or sulfhydryl-containing medium produces nephrotoxic products. These studies show that Compound A is directly toxic to the liver, possibly via P 450 activation, and Compound A can react with sulfhydryls directly to produce a nephrotoxic.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::e41c1ba776f89b130c4c1bdd1a9da078Test
https://pubmed.ncbi.nlm.nih.gov/11665648Test

المؤلفون: Robyn L. Fisher, Klaus Brendel, John Pierre Michaud, A. Jay Gandolfi

المصدر: Toxicology. 105(2-3)

مصطلحات موضوعية: Intracellular Fluid, Chemical compound, Biology, In Vitro Techniques, Toxicology, Chlorobenzenes, Hazardous Substances, Xenobiotics, Rats, Sprague-Dawley, chemistry.chemical_compound, Biotransformation, Species Specificity, Animals, Humans, Drug Interactions, fungi, food and beverages, Microtomy, In vitro, Rats, Inbred F344, Rats, Interaction studies, chemistry, Liver, In vitro system, Slice method, Potassium, Bromobenzenes

الوصف: Precision-cut tissue slices have proven to be a useful in vitro system for biotransformation and toxicity studies. Since tissue slices can be readily prepared from a variety of tissues and species, they can easily be used for interspecies investigations and comparisons. Furthermore, slices can be readily prepared from human tissue, thus comparisons (extrapolation) can be made between laboratory animals and humans. Slices can also be used to examine the toxic interactions of chemicals in vitro. It is important to use the correct experimental design to demonstrate toxic interactions and to assure that the tissue slices are properly exposed to the chemicals. Overall, tissue slices offer a valid in vitro system for performing species comparisons and chemical-chemical interaction studies.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::5c0e063a1c89bceb8b230b523094b61fTest
https://pubmed.ncbi.nlm.nih.gov/8571365Test

المؤلفون: A. Jay Gandolfi, Robyn L. Fisher, I. Glenn Sipes, Steven J. Hasal, Klaus Brendel

المصدر: Humanexperimental toxicology. 14(5)

مصطلحات موضوعية: 0301 basic medicine, Male, Adolescent, Liver cytology, Health, Toxicology and Mutagenesis, Metabolite, Glucuronates, Biology, In Vitro Techniques, Toxicology, Organ culture, Chlorobenzenes, Dichlorobenzene, Rats, Sprague-Dawley, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Species Specificity, Animals, Humans, Cysteine, Cysteine metabolism, Binding Sites, 030102 biochemistry & molecular biology, General Medicine, Metabolism, In vitro, Rats, Inbred F344, Rats, chemistry, Biochemistry, Liver, 030220 oncology & carcinogenesis, Protein Biosynthesis, Toxicity, Potassium, Sulfatases

الوصف: 1 Precision-cut liver slices, prepared from Sprague- Dawley and Fischer-344 rats and donated human liver tis sue, were used to identify differences in 1,2-dichloroben zene (1,2-DCB), 1,3-dichlorobenzene (1,3-DCB) and 1,4- dichlorobenzene (1,4-DCB) metabolism and how it may relate to toxicity. 2 Rat and human liver slices were incubated with 1 mM of either dichlorobenzene to determine metabolism and toxi city, at 2 and 6 h of organ culture. 3 The human liver slices metabolised the dichloroben zenes to a greater extent than those from either of the rat strains. Liver slices from the Fischer-344 strain had a higher metabolic rate than the slices from the Sprague- Dawley rat strain. 4 The metabolic rate of dichlorobenzene isomers did not consistently correlate with its toxicity. For example, human slices did not exhibit any hepatotoxicity, even though they metabolised these compounds to a greater extent than either rat strain. 5 Cross species covalent binding did not correlate with toxicity endpoints measured in this study. 6 The phase two metabolite profiles for each of the iso mers in human and rat slices were similar in that the glu tathione-cysteine conjugate was the major metabolite. 7 The use of an in vitro system which utilises human liver slices might provide an important bridge between animal derived data and the human situation.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::056e8ec00e8406102e73cc074bc535faTest
https://pubmed.ncbi.nlm.nih.gov/7612303Test

المؤلفون: David Johnson, Carlos L. Krumdieck, Roberta L. McKee, Klaus Brendel, Victor J. Hruby, A. Jay Gandolfi, D. Trivedi

المصدر: Journal of Pharmacological Methods. 19:339-354

مصطلحات موضوعية: medicine.medical_specialty, Glycogenolysis, In Vitro Techniques, Peptide hormone, Biology, Carbohydrate metabolism, Glucagon, chemistry.chemical_compound, Internal medicine, Cyclic AMP, medicine, Animals, Protein kinase A, Pharmacology, Glycogen, Microtomy, Hormones, Liver Glycogen, Rats, Glucose, Endocrinology, Liver, chemistry, Second messenger system, Protein Kinases, Intracellular

الوصف: A nonrecirculatory perfusion system for precision-cut rat liver slices has been developed and utilized for investigating hormone-regulated hepatic glucose metabolism. In this system, slices are cultured in a highly controlled environment and exhibit excellent retention of viability as judged by their maintenance of intracellular potassium and glycogen contents. Using this system, the complex physiological phenomenon of hormone-regulated glycogenolysis was investigated at both extra- and intracellular sites. Specifically, the sensitive responses of intracellular cyclic AMP (cAMP) production, activation of cyclic AMP-dependent protein kinase, and production of glucose upon glucagon stimulation have been measured. The maximal responses observed for these parameters were either equal to or greater than those previously reported for either isolated hepatocytes or perfused livers, demonstrating the sensitivity of this technique. Upon dose-response examination of glucagon challenge, it was observed that high doses of glucagon (greater than 16 nM) stimulate glucose production by activating the cAMP-second messenger cascade. In contrast, low doses (less than 4 nM) stimulate this process without production of intracellular cAMP or activation of cAMP-dependent protein kinase, suggesting the operation of cAMP-independent messenger. Since this system permits measurements of parameters common to many cellular processes, this methodology is suitable for addressing both pharmacological and toxicological questions.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::a6aa72f2cacb0140678ab6f53ac8ecd4Test
https://doi.org/10.1016/0160-5402Test(88)90007-1