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At least 451 records · Page 25Linked to original sources
PubMed1983

Hamster hepatocytes in culture as a model for acetaminophen toxicity studies with inhibitors of drug metabolism.

A hamster hepatocyte system was developed for use in studying the toxicity of acetaminophen (APAP). The cells were isolated and placed in culture conditions in petri dishes containing a film of collagen. Hepatocytes, after attachment to collagen, were exposed for various periods of time to different concentrations of APAP. Hepatocytes exposed to APAP exhibited concentration- and time-dependent GSH depletion followed by cytoplasmic enzyme leakage and an increase in malondialdehyde content (TBA-reactive material). These effects were reduced by the drug metabolism inhibitors metyrapone, piperonyl butoxide, and dithiocarb. Removal of APAP and its unbound metabolites from cells prior to 1.5 hr followed by culture in drug-free medium resulted in no observable damage to the cells over a 24-hr period. Removal of drug after longer exposure times followed by culture in fresh medium resulted in eventual cell damage. This finding showed that deleterious changes caused by APAP occurred over a 1.5-hr period after which eventual hepatocyte damage could not be reversed by removal of the drug. Further experiments showed that metyrapone and dithiocarb had some protective effect when added after APAP had been completely removed from damaged cells. This result indicates that these agents have a protective action separate from, and in addition to, their ability to inhibit APAP oxidation via cytochromes P-450.

Acetaminophen↗
PubMed1988

Use of an in vitro system to study the effects of lead on astrocyte-endothelial cell interactions: a model for studying toxic injury to the blood-brain barrier.

We investigated the effect of inorganic lead on the interaction of immature rat astrocytes and bovine adrenal endothelial cells. The two cell types were cultured alone and in coculture in the presence or absence of lead acetate for up to 1 week. A battery of cell specific markers was used for cell identification. Newborn Sprague-Dawley rat brain astrocytes were more sensitive than bovine adrenal endothelial cells to the cytotoxic effects of 10-50 microM lead acetate, as demonstrated by a decrease in cell number and by the presence of intracellular vacuoles and detached cells. The number of astrocytes decreased to 50% of control after 4 days in culture at a concentration of 10 microM lead. In contrast, a mitogenic effect of lead was observed on the endothelial cells at this concentration, with an increase in cell number to 110% of control. In coculture, the two cell types demonstrated a distinctive cellular organization and the astrocytes were less sensitive to the cytotoxic effects of lead than when they were cultured alone. A lead-enhanced induction of a neural capillary enzyme activity, gamma-GTP, was detected histochemically in the coculture system. These results are consistent with a maturing or differentiating effect of the endothelial cells on the astrocytes, making them less susceptible to lead and mature enough to induce gamma-GTP activity in the endothelial cells.

Adrenal Glands↗
PubMed1983

Effect of sodium fluorescein on neurite outgrowth from the retinal explant culture: an in vitro model for retinal toxicity.

Effect of sodium fluorescein was examined on neurite outgrowth from the retinal explants of chick embryos cultured with chicken gizzard extract, containing macromolecules which promote neurite outgrowth. A dose more than 0.5 mg/ml of fluorescein completely prevented the neurite outgrowth from the retinal explants. The minimum dose of toxic effect of fluorescein on the neurite outgrowth was about 0.2 mg/ml. The fluorescein also caused lysis of pre-existing neurites which had been fully extended by gizzard extract.

Animals↗
PubMed1985

Primary cultures of adult rat hepatocytes--a model for the toxicity of histamine H2-receptor antagonists.

Oxmetidine, a potent histamine H2-receptor antagonist, is cytotoxic to primary cultures of adult rat hepatocytes. The criteria of cellular injury included leakage of cytoplasmic enzymes into the culture medium, inhibition of protein synthesis and measurement of oxygen consumption by freshly isolated hepatocytes. These parameters were correlated with morphological changes in the cells as judged by inverted phase-contrast microscopy. In contrast, two other histamine H2-receptor antagonists, cimetidine and ranitidine, caused only minor changes in these parameters of cytotoxicity. The extent of injury observed with oxmetidine was both time and concentration dependent and was similar in hepatocytes maintained in culture for 2, 24 or 48 h. Prior treatment of rats with phenobarbital or beta-naphthoflavone did not influence oxmetidine-induced cytotoxicity. Inhibitors of cytochrome P-450-mediated monooxygenase activity had little effect on oxmetidine-induced injury with the exception of metyrapone, which was shown to inhibit the observed cytotoxicity by a mechanism other than inhibition of monooxygenase activity. In contrast, the injury could be potentiated by L-ethionine, an antimetabolite which reduces cellular ATP levels, suggesting that oxmetidine induces cytotoxic effects as a consequence of an interaction with intermediary energy metabolism.

Animals↗
PubMed2005

Simultaneous effect of lead and cadmium on granulosa cells: a cellular model for ovarian toxicity.

Lead (Pb) and cadmium (Cd) are known reproductive toxicants, which accumulate in granulosa cells of the ovary. Female Charles foster rats were treated with sodium acetate (control), lead acetate and cadmium acetate either alone or in combination at a dose 0.05 mg/kg body weight intra-peritoneally for 15 days daily. Animals were killed at proestrous stage and granulosa cells were isolated from the ovaries. Binding of (125)I-luteinizing hormone ((125)I-LH), (125)I-follicle stimulating hormone ((125)I-FSH) and 17beta-hydroxysteroid dehydrogenase activity were measured. As these receptors are localized on the surface of the cell membrane, we also estimated the membrane parameters of these cells. Our results demonstrated that both lead and cadmium caused a significant reduction in gonadotropin binding, which altered steroidogenic enzyme activity of granulosa cells. These changes exhibited a positive correlation with membrane changes of the granulosa cells.

Algorithms↗
PubMed1985

Carbon tetrachloride toxicity as a model for studying free-radical mediated liver injury.

A single dose of CCl4 when administered to a rat produces centrilobular necrosis and fatty degeneration of the liver. These hepatotoxic effects of CCl4 are dependent upon its metabolic activation in the liver endoplasmic reticulum to reactive intermediates, including the trichloromethyl free radical. Positive identification of the formation of this free radical in vivo, in isolated liver cells and in microsomal suspensions in vitro has been achieved by e.s.r. spin-trapping techniques. The trichloromethyl radical has been found to be relatively unreactive in comparison with the secondarily derived peroxy radical CCl3O2., although each free radical species contributes significantly to the biological disturbances that occur. Major early perturbations produced to liver endoplasmic reticulum by exposure in vivo or in vitro to CCl4 include covalent binding and lipid peroxidation; studies of these processes occurring during CCl4 intoxication have uncovered a number of concepts of general relevance to free-radical mediated tissue injury. Lipid peroxidation produces a variety of substances that have high biological activities, including effects on cell division; many liver tumours have a much reduced rate of lipid peroxidation compared with normal liver. A discussion of this rather general feature of liver tumours is given in relation to the liver cell division that follows partial hepatectomy.

Animals↗
PubMedDate not supplied

[Studying the hepatoprotector effect of bemithyl on a model of chronic toxic liver damage].

A prophylactic and therapeutic introduction of the synthetic adaptogen bemithyl (2-ethylthiobensimidasole hydrobromide) produces a hepatoprotector effect in rats with experimental cirrhosis. The drug exhibits an anticytolytic activity, restores liver participation in the pigment exchange, and normalizes the function of the microsomal oxidation system responsible for the metabolism of xenobiotics. The treatment with bemithyl also leads to a certain improvement of a histologic picture of the damaged liver and to a decrease in the degree of fibrosis. The drug is also capable of increasing the activity of the antioxidant system and inhibiting the process of lipid peroxidation of proteins and lipids in the liver.

Animals↗
PubMed1988

Long-term bone marrow culture as a model for host toxicity: the effect of methotrexate on hematopoiesis and adherent layer function.

Long-term bone marrow culture was used to examine the hematopoietic toxicity of the chemotherapeutic agent methotrexate. A dose-related suppression in myelopoiesis was seen when cultures were treated with 10(-3), 10(-4), or 10(-5) M methotrexate followed by folinic acid rescue. Differential counts revealed an initial decrease of postmitotic myeloid cells followed by mitotic precursors and myeloid colony-forming units (CFU-C). Myelopoiesis had disappeared by 7-10 days when 10(-3) M methotrexate was studied, by day 21 with 10(-4) M methotrexate, and by day 28 with 10(-5) M methotrexate. Although 10(-3) M methotrexate caused a predictable suppression in myelopoiesis, the effect of 10(-5) M methotrexate was more variable. In some studies this dose caused significant suppression of myelopoiesis, whereas in others less suppression occurred. This provides some evidence for varying host susceptibility to drug. Microenvironmental (adherent layer) cells were also affected by methotrexate. An increase in proliferation of these cells occurred in proportion to the dose of methotrexate added to culture. Methotrexate did not affect the ability of the adherent cells to produce colony-stimulating activity (CSA), but high doses did prevent the layer's ability to support the proliferation of adherent cell-free marrow. These results indicate that long-term bone marrow culture can be used to successfully predict and define chemotherapeutic host toxicity.

Bone Marrow↗
PubMed1985

Fetal thymus organ culture as an in vitro model for the toxicity of 2,3,7,8-tetrachlorodibenzo-p-dioxin and its congeners.

Fetal thymuses from C57BL/6 (B6) and DBA/2J (D2) mice from gestation day 14 or 15 were explanted and grown for 2 and 6 days in culture in the presence of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and a number of its congeners, known ligands of the Ah receptor (Ah, designating genetic locus for aryl hydrocarbon responsiveness). TCDD and 2,3,7,8-tetrachlorodibenzofuran (TCDBF) showed the same toxicity to B6 thymuses with a 50% inhibition of lymphoid development (EC50) at 10(-10) M concentration. 3,3',4,4'-Tetrachloroazoxybenzene (TCAOB) was only 2-10 times less effective, while the EC50 of 3,3',4,4'-tetrachlorobiphenyl (TCB) was around 10(-8) M (100 times higher than that of TCDD). TCBs with chlorine atoms in the position close to the biphenyl bridge were nontoxic even at 10(-5) M concentration. Thymuses exposed to TCDD, TCDBF, and TCAOB in vivo at teratogenic doses given to the mothers and explanted 24-48 hr later were smaller and inhibited in their early in vitro growth, but recovered slowly (less rapid for TCDD) as judged by lymphoid cell counts and [3H]thymidine incorporation. These results indicate a good correlation for this group of compounds between their activity as ligands of the Ah receptor and toxicity in vitro. Other ligands of the Ah receptor, namely 3-methylcholanthrene and beta-naphthoflavone, were inactive at the highest concentrations tested (10(-6) M). Thymuses from D2 mice, considered Ah receptor-defective, were nonsensitive to TCDD at the concentrations used (up to 3 X 10(-8) M) after 2 days in culture, indicating more than 100 times lower sensitivity as compared to B6 thymuses. After 6 days in culture, their sensitivity was however only 1 order of magnitude lower than that of B6 thymuses. Therefore "low sensitivity" of D2 thymuses may be at least partially overcome by prolonged exposure to TCDD in vitro.

Animals↗