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At least 775 records · Page 43Linked to original sources
PubMed2002

A lead-gill binding model to predict acute lead toxicity to rainbow trout (Oncorhynchus mykiss).

Rainbow trout (Oncorhynchus mykiss, approximately 2 g) were exposed to 0.6-1.0 microM Pb (125-200 microgl(-1)) for 3 h in ion-poor water. Complexing ligands (citrate, ethylenediamine, organic matter (OM)) or competing cations (Ca, Mg, Na) were added to the water. After exposure, trout gills were removed and analyzed for accumulated Pb. From these exposures, a conditional equilibrium binding constant (K) for Pb-gill binding was calculated (log K(Pb-gillPb)=6.0), plus conditional binding constants for cationic competition at the Pb binding sites and for Pb binding to OM in the water. These log K values were entered into the MINEQL+ aquatic chemistry equilibrium program, to calculate binding of Pb by trout gills. Two versions of the Pb-gill binding model were generated, one of which took into account OM quality as indicated by a simple measure of OM aromaticity, the specific absorption coefficient. The two model versions were tested against acute Pb toxicity (as the time to reach 50% fish mortality; LT50) during 1-week exposures of trout to 3.9 microM Pb in water collected from across southern Ontario. Both versions of the model generated highly significant correlations between the LT50 values and gill Pb concentrations calculated from measured exposure water chemistry, with the OM quality version correlating slightly better. Water pH also correlated well with the LT50 values, because the Pb exposures were in the pH range (7-8) where there is a nearly linear relationship between water pH and inorganic complexation of Pb. Advantages of the Pb-gill binding model include its completeness and the flexibility inherent in its conceptual framework, for example the inclusion of competition by Ca and H(+) for Pb binding sites on gills, and inclusion of complexation of Pb in the water column by natural OM and by carbonate.

Animals↗
PubMedDate not supplied

Metabolism and testicular toxicity of 1,3-dinitrobenzene in the rat: evaluation of the stage-synchrony model.

Because many testicular toxicants cause damage to specific stages of spermatogenesis, the present study has investigated the utility of a model in which the testis is synchronized to contain only a few closely related spermatogenic stages. The susceptibility of different stages to 1,3-dinitrobenzene (1,3-DNB) toxicity was investigated in rats, the testes of which had been stage synchronized by a vitamin A depletion/repletion (VADR) procedure. 1,3-DNB (25 mg/kg, IP) or vehicle was injected 58, 61, or 78 d after vitamin A readministration, and testicular histopathology was evaluated 48 h later. At the time of sacrifice, testes in the three groups were synchronized to stages I-VI, VII-IX, or X-XIV+I. The data indicated that tubules in all stages of spermatogenesis, in both synchronized and unsynchronized animals, demonstrated histopathologic changes in response to 1,3-DNB. However, the lesion seen in synchronized animals was more severe and less stage specific than that seen in weight-matched, unsynchronized animals. This increase in degree of susceptibility could be partially explained by differences in toxicokinetics. Stage-synchronized testes could provide unique insights into stage-specific cellular and molecular events, especially for in vitro studies where the stage enrichment could be maximally exploited. However, results obtained from in vivo toxicity studies using animals subjected to VADR should be interpreted carefully in light of the confounding physiologic/metabolic perturbations potentially induced by the VADR procedure.

Animals↗
PubMed1999

Effectiveness and toxicity of gentamicin in an experimental model of pyelonephritis: effect of the time of administration.

Temporal variations in the renal toxicity of aminoglycosides have been reported for experimental animals as well as for humans. In fact, maximal renal toxicity of aminoglycosides was observed when the drug was given during the rest period, while a lower toxicity was observed when the drug was injected during the activity period. The aim of the present study was to evaluate temporal variations in the effectiveness and renal toxicity of gentamicin in an experimental model of pyelonephritis in rats. The experiments were carried out with female Sprague-Dawley rats (185 to 250 g). They had free access to food and water throughout the study and were maintained on a 14-h light-10-h dark cycle. Animals were divided into four groups corresponding to the respective time of induction of pyelonephritis and treatment: 0700, 1300, 1900, and 0100 h. Pyelonephritis was induced by a direct inoculation of Escherichia coli (10(7) to 10(8) CFU) in the left kidney. Animals were treated for 3 and 7 days with a single daily dose of gentamicin (20 and 40 mg/kg of body weight, respectively) or saline (NaCl, 0.9%) at either 0700, 1300, 1900, or 0100 h. Animals treated at 0100 h for 3 days with gentamicin (20 mg/kg) showed a significantly lower number of bacteria in their kidneys than did all other groups (P < 0.01). After 7 days of treatment, the efficacy, evaluated by the log CFU per gram of tissue and by the percentage of sterilized kidneys, was also higher when gentamicin was administered at 0100 h. The beta-galactosidase and the N-acetyl-beta-D-glucosaminidase activities were significantly higher in urine of rats given gentamicin at 1300 h than in urine of rats treated at another time of day (P < 0.05). Gentamicin injected at 1300 h induced a significantly greater increase of [3H]thymidine incorporation into DNA of renal cortex (P < 0.01), a significantly greater inhibition of sphingomyelinase activity (P < 0.05), and significantly more histopathological lesions than the same dose injected at another time of the day. Creatinine and blood urea nitrogen levels in serum were significantly higher (P < 0.05) and the creatinine clearance was significantly lower (P < 0.05) when gentamicin was injected at 1300 h than when it was injected at another time of day. Our data suggest temporal variations in both the toxicity and the effectiveness of gentamicin, the drug being more effective and less toxic when injected during the activity period of the animals.

Animals↗
PubMed1996

Model-based QSAR for ionizable compounds: toxicity of phenols against Tetrahymena pyriformis.

The previously described pseudo-equilibrium model for kinetics of distribution of extraneous chemicals in biological systems has been used for the development of the QSAR equation expressing toxicity of phenols against Tetrahymena pyriformis as a non-linear function of their hydrophobicity and acidity. The model assumes binding of all the tested compounds to a single class of the receptors (i.e., it does not discriminate between possible narcotic and respiratory uncoupling modes of action of phenols) with the association constant related to the electronic structure of the molecules rather than to their hydrophobicity. Non-linear regression analysis revealed satisfying agreement between the model and published biological data measured after a single dose.

Animals↗
PubMed2001

The acute and chronic toxicity of cadmium and zinc to two hydra species.

The potential of two hydra species, Hydra vulgaris (pink) and Hydra viridissima (green), for use as invertebrate models for toxicity testing of waterborne metals was investigated. The acute and subchronic toxicities of cadmium (a nonessential metal) and zinc (an essential metal) were determined. Results showed that both the hydra species were more sensitive to cadmium than to zinc, and that green hydra were more sensitive than pink hydra. The mean (SE) 96 h LC50 values of cadmium and zinc for pink hydra were 83 (8.5) and 2300 (150) micrograms/L, respectively. For green hydra, the respective 96 h LC50 values for cadmium and zinc were 3.0 (0.0) and 935 (46.5) micrograms/L. The respective 7-day no-observed-effect-concentrations (NOEC) and lowest-observed-effect-concentrations (LOEC) for pink hydra were < 13 and 13 micrograms/L for cadmium, and < 250 and 250 micrograms/L for zinc. The respective 7-day NOEC and LOEC values for green hydra were 0.4 and 0.8, microgram/L for cadmium, and 38 and 75 micrograms/L for zinc. Neither 1, 2, or 3 x 90-min pulse-exposures to 0.4, 0.8, or 1.5 micrograms/L of cadmium had any significant deleterious effect on total green hydra numbers after seven days in clean water. Green hydra appeared to be excellent freshwater invertebrate models for testing dissolved metals based on their sensitivity and the ability to rapidly assess population reproduction in the laboratory.

Animals↗
PubMed2006

A comparison of vasopressin and glucagon in beta-blocker induced toxicity.

OBJECTIVE: We compared the efficacy of vasopressin and glucagon in a porcine model of beta-blocker toxicity. Our primary outcome was survival over 4 hours. METHODS: Sixteen pigs received a 1-mg/ kg bolus of propranolol IV followed by continuous infusion at 0.25 mg/kg/minute. Toxicity was defined as a 25% decrease in the product of heart rate (HR) and mean arterial pressure (MAP), at which point 20 mL/kg normal saline was rapidly infused. Each pig was randomly assigned to receive either vasopressin or glucagon after the saline bolus. The vasopressin group received a continuous infusion at 0.0028 U/kg/minute, titrated up to a maximum of 0.014 U/ kg/minute. The glucagon group received a 0.05-mg/kg bolus followed by continuous infusion at 0.15 mg/kg/hour. The HR, MAP, systolic BP (SBP), cardiac output (CO), glucose, and pH were monitored for 4 hours from toxicity or until death. RESULTS: One pig survived at 4 hours (vasopressin group). Analysis of the 4-hour Kaplan-Meier survival curves found no differences between the groups (log-rank test 0.059, p = 0.81). No overall differences were identified in MAP, systolic BP, cardiac output, glucose, pH, or HR. However, over the first hour MAP and SBP were significantly higher in the vasopressin group (p = 0.004, p = 0.006, respectively). CONCLUSION: In this beta-blocker toxicity model, there were no differences in the survival curves between vasopressin- and glucagon-treated pigs during a 4-hour analysis period. No overall differences were noted in MAP, systolic BP, CO, HR, pH, or glucose levels, although vasopressin treatment yielded higher MAP and systolic BP early in resuscitation.

Adrenergic beta-Antagonists↗
PubMed1995

Investigations into the molecular basis of meningococcal toxicity for human endothelial and epithelial cells: the synergistic effect of LPS and pili.

Using human umbilical vein endothelial cells as an in vitro model of toxicity, it was found that Neisseria meningitidis, Neisseria gonorrhoeae, Neisseria lactamica and Neisseria sicca caused damage to these cells, in contrast to the lack of cytotoxicity exhibited by Haemophilus influenzae type b. N. meningitidis was also found to be toxic for human epithelial cells. The major toxic factor of N. meningitidis was found to be a heat-stable component of outer membrane vesicles, and could be inhibited by polymyxin B, suggesting that lipopolysaccharide plays a major role in toxicity. However, the toxicity mediated by lipopolysaccharide was modulated significantly by pilus-dependent adherence. Intra-strain variants expressing altered pilins which exhibited different levels of adherence to epithelial and endothelial cells were used to study the role of pilus. The degree of toxicity observed correlated with their relative level of adherence to cultured cells. In contrast, Opc-dependent increased adherence did not result in increased toxicity for endothelial cells, suggesting that pili have a synergistic effect, contributing to the overall damage.

Bacterial Adhesion↗
PubMed2000

Models for estimating the non-specific toxicity of organic compounds in short-term bioassays.

The solvation parameter model is used to construct equations for the estimation of the non-specific toxicity of neutral organic compounds to five organisms used for short-term toxicity testing. For the bacteria Vibrio fischeri (Microtox test) and Pseudomonas putida, the protozoan Tetrahymena pyriformis (Tetratox test), the green alga Scendesmus quadricauda and the brine shrimp Artemia salina, the main factors resulting in increased non-specific toxicity are size (dominantly) and lone-pair electron interactions, with hydrogen-bond basicity the most important solute property reducing toxicity. Species differences in relative non-specific toxicity are largely related to differences in cohesion and hydrogen-bond acidity of the biomembranes. The models for non-specific toxicity are proposed as an alternative to the octanol-water distribution constant for the determination of baseline toxicity. Failure of the octanol-water distribution constant to model non-specific toxicity is quantitatively explained by its inability to adequately characterize the sorption properties of the biomembranes for compounds with varied properties.

Animals↗
PubMed2005

Concomitant chemotherapy and radiation therapy for cancer of the uterine cervix.

BACKGROUND: The National Cancer Institute (USA) alert in February 1999 stated that concomitant chemoradiotherapy should be considered for all patients with cervical cancer, based on evidence from five randomised controlled trials (RCTs). OBJECTIVES: To review all known RCTs comparing concomitant chemotherapy and radiation therapy with radiotherapy for locally advanced cervical cancer. SEARCH STRATEGY: We searched electronic databases, trials registers and reference lists of published trial reports and review articles were also searched. SELECTION CRITERIA: This review includes RCTs in cervical cancer comparing concomitant chemoradiation with radiotherapy in the experimental arm. Trials allowing further adjuvant chemotherapy or hydroxyurea were included. Trials using radiosensitisers or radioprotectors in the experimental arm were excluded. DATA COLLECTION AND ANALYSIS: Two authors reviewed trials for inclusion and extracted data. For meta-analyses of time-to-event outcomes (survival, progression-free survival), a hazard ratio (HR) was extracted or estimated from trial reports, where possible. Only overall rates of local and distant recurrence were presented in many reports so only odds ratios (OR) of recurrence rates could be calculated, which takes no account of time to recurrence or censoring. Few trials reported acute toxicity adequately, but where possible ORs were calculated for the main types and severities of acute toxicity. The HRs and ORs for individual trials were combined across all trials, using the fixed effect model. Late toxicity was rarely described in sufficient detail so could only be reviewed qualitatively. MAIN RESULTS: The original review was based on nineteen trials (17 published and two unpublished) including 4580 patients. This update includes twenty four trials (21 published, 3 unpublished) and 4921 patients, although due to patient exclusion and differential reporting 61% to 75% were available for the analyses. The review strongly suggests chemoradiation improves overall survival and progression free survival, whether or not platinum was used with absolute benefits of 10% and 13% respectively. There was, however, statistical heterogeneity for these outcomes. There was some evidence that the effect was greater in trials including a high proportion of stage I and II patients. Chemoradiation also showed significant benefit for local recurrence and a suggestion of a benefit for distant recurrence. Acute haematological and gastrointestinal toxicity was significantly greater in the concomitant chemoradiation group. Late effects of treatment were not well reported and so the impact of chemoradiation on these effects could not be determined adequately. Treatment-related deaths were rare. AUTHORS' CONCLUSIONS: Concomitant chemoradiation appears to improve overall survival and progression-free survival in locally advanced cervical cancer. It also appears to reduce local and distant recurrence suggesting concomitant chemotherapy may afford radiosensitisation and systemic cytotoxic effects. Some acute toxicity is increased, but the long-term side effects are still not clear.

Combined Modality Therapy↗
PubMed2006

Low molecular weight dextran sulfate: a strong candidate drug to block IBMIR in clinical islet transplantation.

The instant blood-mediated inflammatory reaction (IBMIR) is triggered in clinical islet transplantation when human pancreatic islets come in contact with blood and may explain the initial tissue loss associated with this procedure. Low molecular weight dextran sulfate (LMW-DS; MM 5000), today available for clinical use, inhibits both complement and coagulation activation. In a tubing loop model, LMW-DS at concentrations ranging from 0.01 to 1 g/L showed a dose-dependent inhibition of IBMIR with an inhibition of coagulation and complement activation and less consumption of platelets and other blood cells. In blood or plasma APTT was demonstrated to be an excellent method for monitoring the LMW-DS concentration both in vitro and in vivo in a nonhuman primate model. The toxicity was assessed using a glucose challenge test and the pharmacokinetics was tested in the nonhuman primate model. Here, we present a tentative protocol for using LMW-DS in clinical islet transplantation.

Anticoagulants↗
PubMedDate not supplied

Augmented antitumor effects of combination therapy with interleukin-12, cisplatin, and tumor necrosis factor-alpha in a murine melanoma model.

Interleukin-12 (IL-12) has demonstrated antitumor activity in many murine tumor models. However, toxic effects resulting from treatment with IL-12 have been also described. Combining IL-12 with other antineoplastic agents could potentiate its antitumor efficacy and, furthermore, could minimize its toxicity by reducing the doses necessary to achieve the antitumor activity. We examined in a murine melanoma model the efficacy of combination tumor chemo-immunotherapy based on administration of IL-12, cisplatin (CDDP), and tumor necrosis factor-alpha (TNF-alpha). In the current study pairs of: IL-12 + CDDP and IL-12 + TNF-alpha, showed stronger antitumor activity than either agent given alone. Furthermore, combination tumor therapy with IL-12 + CDDP + TNF-alpha was more effective at retarding local tumor growth than either IL-12 + CDDP, IL-12 + TNF-alpha or CDDP + TNF-alpha combination therapies. Our observations indicate that combining of CDDP with IL-12 and IL-12 with TNF-alpha as well as using the triple combination of CDDP, IL-12 and TNF-alpha could be beneficial in tumor therapy.

Animals↗
PubMed2006

Opercular epithelial cells: a simple approach for in vitro studies of cellular responses in fish.

This study evaluated the efficacy of fish opercular external (skin) and inner (opercular membrane) epithelium as an in vitro model for toxic and other substances studies. The rainbow trout (Oncorhynchus mykiss) operculum was cultured in 12-well dishes containing sterile Leibovitz 15 (L-15) supplemented with glutamine medium during 24h at 9 degrees C, and the effect of copper, a toxic agent, and/or cortisol, an endogenous agent, on the epithelial cells was analyzed using light microscopy techniques. The opercula were submitted to four treatments: (i) control (Cont), L-15 medium only, (ii) 0.28 microM cortisol (Cort), (iii) 100 microM CuSO(4) (Cu), and (iv) 0.28 microM cortisol+100 microM CuSO(4) (Cort-Cu). The tissue condition after 24h incubation was analyzed by staining the mucous cells for neutral and acid mucosubstances. Cellular necrosis was evaluated by measuring the lactate dehydrogenase (LDH) leakage at 12 and 24h incubation. Cellular proliferation, apoptosis, metallothionein (MT) and glucocorticoid receptor (GR) expression were evaluated by immunohistochemistry. The LDH leakage was higher and the proliferating cell nuclear antigen (PCNA) positive-stained cells were lower in Cu treatment in both, epidermis and opercular membrane. Apoptotic cells in the opercular membrane were higher in the Cort and Cort-Cu treatments while, in the epidermis, they were higher in Cu and Cort-Cu treatments. GR-positive stained cells decreased significantly in all treatments in both epithelia and the MT-positive cells increased in the Cu and Cort-Cu treated groups. Copper showed to be a potent toxic stressor killing the cells via necrosis, decreasing the number of PCNA-positive cells and inducing MT synthesis while cortisol did not affect the MT synthesis, although it might stimulate apoptosis. The results are evidence that the opercular epithelia serve as a suitable model for studying in vitro effects of toxic agents, as well as endogenous factors on the cellular responses without interference of the physiological state of fish being useful to predict in vivo toxicity.

Animals↗
PubMed1984

Studies on the effect of 4-methylpyrazole on methanol poisoning using the monkey as an animal model: with particular reference to the ocular toxicity.

Young cynomolgus monkeys (Macaca fascicularis) were chosen as a model to investigate the ocular toxicity in animals poisoned with methanol and treated with 4-methylpyrazole (4-MP). The metabolism of methanol in the monkey was investigated after administration of 4-MP. Plasma levels of methanol, formic acid, 4-MP and 4-hydroxy-MP (4-OH-MP) were determined. After intramuscular injection, 4-MP was rapidly absorbed and depressed the elimination rate of methanol as well as the accumulation of formate in the blood. The results show the same great individual variations in monkeys as in humans regarding the susceptibility to methanol poisoning. Administration of a single dose of 5 g/kg induces a serious intoxication in most monkeys, causing death to some of them. Two monkeys receiving a single dose of 6 g/kg of methanol developed a serious initial inebriation and were treated with 4-MP. These monkeys survived and showed no signs of toxicity on ocular examinations which included ophtalmoscopy and electroretinogram (ERG) recordings.

Alcohol Oxidoreductases↗
PubMed1989

Local immunosuppression with reduced systemic toxicity in a canine renal allograft model.

We compared the efficacy of continuous intraarterial versus intravenous 6-mercaptopurine (6-MP) infusion in a mongrel canine renal allograft model with regard to overall survival, incidence of systemic and renal toxicity, and systemic drug exposure. Arterial anastomoses were done end-to-end, and infusion catheters were placed in the iliac artery or vena cava and connected to a subcutaneously placed programmable pump. A dose of 0.5 mg/kg/day 6-MP did not prolong survival over heparin-treated or untreated controls (MST = 7 days for both groups) when administered either locally or systemically. However, 0.75 mg/kg/day 6-MP i.a. (MST = 20 days) significantly prolonged survival over both untreated (P = 0.007) and heparin-treated controls (P = 0.02), with all dogs eventually dying of rejection. In contrast, 0.75 mg/kg/day i.v. (MST = 7 days) failed to prolong survival over controls (P greater than 0.1) and produced death from systemic toxicity in 3 of 7 animals. Six of 7 dogs receiving 2.0 mg/kg/day 6-MP i.a. (MST = 12 days) developed azotemia secondary to drug-induced nephrotoxicity. Identical renal histologic changes occurred in the same time frame in autotransplants treated similarly. Of 7 animals receiving 2.0 mg/kg/day i.v. (MST = 12 days), 5 died from early, severe systemic drug toxicity and 2 from early rejection. During 6-MP infusion at 0.5 mg/kg/day, systemic exposure was significantly less in the locally treated than in the systemically treated dogs when Cr concentrations were normal or moderately elevated (P less than 0.0005 and P = 0.01, respectively) but not when renal function became severely impaired (P = 0.34). In contrast to i.v. infusion, i.a. 6-MP delivery dissociated immunosuppressive efficacy from systemic toxicity, supporting previous work demonstrating high first-pass renal elimination of 6-MP. We conclude that tightly controlled local delivery of an immunosuppressive agent can effectively prolong graft survival with reduced systemic toxicity in a large animal model employing a pump/catheter system applicable to man.

Animals↗
PubMed2000

Models of schedule dependent haematological toxicity of 2'-deoxy-2'-methylidenecytidine (DMDC).

OBJECTIVE: DMDC (2'-deoxy-2'-methylidenecytidine) is-a potential antitumour deoxycytidine analogue of cytosine arabinoside. The major dose-limiting toxicity of DMDC is haematological depression, particularly neutropenia, and therefore quantitative exposure-toxicity relationships for DMDC are warranted. METHODS: Data on the survival fraction at nadir of leukocytes, neutrophils and platelets from 66 patients receiving a once-daily regimen and 85 patients receiving a twice-daily regimen of DMDC were related to DMDC concentration-time profiles using area under the plasma concentration-time curve (AUC), threshold and general models. A semiphysiological model of neutrophils versus time after DMDC administration included transient compartments to imitate the differentiation stages in the bone marrow. RESULTS: The relationship between plasma DMDC concentration-time profiles and the haematological toxicity at nadir was best described using an AUC-dependent model with separate functions for once- and twice-daily dosing, indicating schedule dependence of DMDC effects, even if differences in treatment duration had a similar explanatory value. Twice-daily dosing was associated with greater toxic effects than once-daily dosing. The AUC required for a 70% reduction in the neutrophils was 16 mg.h/l and 4.2 mg.h/l for the once- and twice-daily regimens, respectively. The semiphysiological model included nine proliferating transient compartments that were sensitive to DMDC in a schedule-dependent manner, five non-mitotic, non-sensitive compartments and one compartment for circulating neutrophils. CONCLUSIONS: The haematological toxicity of DMDC is schedule dependent. The survival fractions of leukocytes, neutrophils and platelets are predicted to be lower when given on a twice-daily regimen than on a once-daily regimen. A semiphysiological model with transient compartments successfully described the entire time course of neutropenia after DMDC administration.

Antineoplastic Agents↗
PubMed2007

A comprehensive model for reproductive and developmental toxicity hazard identification: I. Development of a weight of evidence QSAR database.

A weight of evidence (WOE) reproductive and developmental toxicology (reprotox) database was constructed that is suitable for quantitative structure-activity relationship (QSAR) modeling and human hazard identification of untested chemicals. The database was derived from multiple publicly available reprotox databases and consists of more than 10,000 individual rat, mouse, or rabbit reprotox tests linked to 2134 different organic chemical structures. The reprotox data were classified into seven general classes (male reproductive toxicity, female reproductive toxicity, fetal dysmorphogenesis, functional toxicity, mortality, growth, and newborn behavioral toxicity), and 90 specific categories as defined in the source reprotox databases. Each specific category contained over 500 chemicals, but the percentage of active chemicals was low, generally only 0.1-10%. The mathematical WOE model placed greater significance on confirmatory observations from repeat experiments, chemicals with multiple findings within a category, and the categorical relatedness of the findings. Using the weighted activity scores, statistical analyses were performed for specific data sets to identify clusters of categories that were correlated, containing similar profiles of active and inactive chemicals. The analysis revealed clusters of specific categories that contained chemicals that were active in two or more mammalian species (trans-species). Such chemicals are considered to have the highest potential risk to humans. In contrast, some specific categories exhibited only single species-specific activities. Results also showed that the rat and mouse were more susceptible to dysmorphogenesis than rabbits (6.1- and 3.6-fold, respectively).

Abnormalities, Drug-Induced↗
PubMed1989

The role of GSH depletion and toxicity in hydroquinone-induced development of enzyme-altered foci.

Hydroquinone (HQ) may activate oxygen via redox cycles in biological systems and may also deplete glutathione (GSH). Both these reactions are potentially harmful, and we have studied their possible involvement in hydroquinone-induced development of gamma-glutamyltranspeptidase (GGT)-positive enzyme-altered foci in rat liver. The effect of HQ was compared to the effect of duroquinone, catechol, resorcinol and phenol. The dose was 100 mg/kg per day and the test substances were administered for 7-12 weeks in these foci experiments. HQ gave an increased number of foci and increased the foci volume, while none of the other compounds had any significant effect on these parameters. HQ, duroquinone and resorcinol were also tested at a higher dose level (200 mg/kg per day), but this dose gave a lower number of foci than the 100-mg dose. HQ, duroquinone and catechol induced single-strand breaks in hepatic DNA. Single doses of HQ (200 mg/kg) increased malondialdehyde excretion in urine, indicating in vivo lipid peroxidation. Duroquinone, phenol and resorcinol were negative with respect to malondialdehyde excretion. Catechol could not be properly tested as the 200-mg dose killed several animals. HQ and catechol induced hepatic ornithine decarboxylase activity. This effect was correlated to GSH depletion. An in vitro model for toxicity studies with hepatocytes from carcinogen-treated rats was also used. In this model HQ could be shown to be selectively toxic to GGT-negative cells in the presence of extracellular GSH. The toxicity was preceded by a rapid depletion of GSH. Catechol also depleted GSH and could be shown to be selectively toxic, but higher concentrations than those used for HQ had to be used. Duroquinone, phenol and resorcinol were not selectively toxic to GGT-negative cells. As duroquinone can be regarded as a more potent inducer of redox cycles than HQ, it can be concluded that the foci data provide no evidence for an involvement of redox cycles in HQ induced development of enzyme-altered foci. They suggest that GSH depletion may act to develop enzyme-altered foci, and the in vitro data indicate a mechanism by which GSH depletion and toxicity may induce this effect.

Animals↗
PubMed2005

Inability of tau to properly regulate neuronal microtubule dynamics: a loss-of-function mechanism by which tau might mediate neuronal cell death.

Interest in the microtubule-associated protein tau stems from its critical roles in neural development and maintenance, as well as its role in Alzheimer's, FTDP-17 and related neurodegenerative diseases. Under normal circumstances, tau performs its functions by binding to microtubules and powerfully regulating their stability and growing and shortening dynamics. On the other hand, genetic analyses have established a clear cause-and-effect relationship between tau dysfunction/mis-regulation and neuronal cell death and dementia in FTDP-17, but the molecular basis of tau's destructive action(s) remains poorly understood. One attractive model suggests that the intracellular accumulation of abnormal tau aggregates causes cell death, i.e., a gain-of-toxic function model. Here, we describe the evidence and arguments for an alternative loss-of-function model in which tau-mediated neuronal cell death is caused by the inability of affected cells to properly regulate their microtubule dynamic due to mis-regulation by tau. In support of this model, our recent data demonstrate that missense FTDP-17 mutations that alter amino acid residues near tau's microtubule binding region strikingly modify the ability of tau to modulate microtubule dynamics. Additional recent data from our labs support the notion that the same dysfunction occurs in the FTDP-17 regulatory mutations that alter tau RNA splicing patterns. Our model posits that the dynamics of microtubules in neuronal cells must be tightly regulated to enable them to carry out their diverse functions, and that microtubules that are either over-stabilized or under-stabilized, that is, outside an acceptable window of dynamic activity, lead to neurodegeneration. An especially attractive aspect of this model is that it readily accommodates both the structural and regulatory classes of FTDP-17 mutations.

Cell Death↗