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PubMedDate not supplied

Hepatoma HepG2 cells as a model for in vitro studies on mitochondrial toxicity of antiviral drugs: which correlation with the patient?

Currently, drugs have been synthesised that can significantly delay the course of several viral infections, including those provoked by HBV, HCV or HIV, but that display consistent side effects, including toxicity for organelles such as mitochondria. Several in vitro models and techniques have been developed to analyse the effects of such compounds. HepG2 cells (from human hepatoma) are an excellent model to investigate mitochondrial (mt) toxicity because of their high content of organelles and mtDNA, and actually different investigators are indeed using such cells. Studies in vitro on cell lines are relatively easy, but it is necessary to be careful in the interpretation of data, which are usually obtained on continuously growing, tumour cells, quite different from normal, resting, non-neoplastic cells collected from a patient. Direct analysis of drug-induced mt damage in patients is extremely more complex than that performed using in vitro models because of the difficulty to obtain adequate cells or to have discrete amounts of biological material, the status of the patient at the moment of cell collection, the use of an adequate assay and its correct execution, and finally the possibility to find sex- and age-matched healthy controls as source of reference parameters.

Antiviral Agents↗
PubMed2005

Reduction of acute cisplatin ototoxicity and nephrotoxicity in rats by oral administration of allopurinol and ebselen.

Cisplatin ototoxicity has been associated with the generation of toxic levels of reactive oxygen species (ROS) which can lead to injury or loss of outer hair cells in the organ of Corti, damage to the stria vascularis, and loss of spiral ganglion cells, resulting in permanent hearing loss. In an attempt to reduce the formation of ROS and to bolster the innate oxidative stress defenses of the cochlea, we tested individual and combined formulations of allopurinol, a xanthine oxidase inhibitor, and ebselen, a glutathione peroxidase mimic. We used an acute cisplatin toxicity rat model (16 mg/kg i.p.) to analyze allopurinol and ebselen alone and in combination for their ability to reduce cisplatin associated hearing loss and nephrotoxicity. The results from our studies indicate that a combined formulation of ebselen and allopurinol affords significant protection to the cochlea and kidney from cisplatin toxicity. In the cochlea, protection is dependent on the preservation of outer hair cell number, while in the kidney, protection is associated with the preservation of proximal tubular epithelia. Further evaluation of the chemoprotective effects of ebselen and allopurinol on cisplatin side effects in the presence of tumor appears warranted.

Administration, Oral↗
PubMed2002

Segregation and black/white differences in exposure to air toxics in 1990.

I examined non-Hispanic Black and non-Hispanic White differences in exposure to noncriteria air pollutants in 44 U.S. Census Bureau-defined metropolitan areas with populations greater than one million, using data on air toxics concentrations prepared for the U.S. Environmental Protection Agency as part of its Cumulative Exposure Project combined with U.S. census data. I measured differences in exposure to air toxics through the calculation of a net difference score, which is a statistical measure used in income inequality analysis to measure inequality over the whole range of exposures. The scores ranged from 11.52 to 83.60. In every metropolitan area, non-Hispanic Blacks are more likely than non-Hispanic Whites to be living in tracts with higher total modeled air toxics concentrations. To assess potential reasons for such a wide variation in exposure differences, I performed a multiple regression analysis with the net difference score as the dependent variable. Independent variables initially included were as follows: the dissimilarity index (to measure segregation), Black poverty/White poverty (to control for Black/White economic differences), population density and percentage of persons traveling to work who drive to work (alone and in car pools), and percentage of workforce employed in manufacturing (factors affecting air quality). After an initial analysis I eliminated from the model the measures of density and the persons driving to work because they were statistically insignificant, they did not add to the predictive power of the model, and their deletion did not affect the other variables. The final model had an R(2) of 0.56. Increased segregation is associated with increased disparity in potential exposure to air pollution.

Air Pollutants↗
PubMedDate not supplied

Toxicity of chronic spinal analgesia in a canine model: neuropathologic observations with dezocine lactate.

The chronic spinal toxicity of dezocine lactate was investigated in mongrel dogs. Dogs received chronic intrathecal infusion from implanted infusion pumps for 28-136 days. Infusion of saline via intrathecal catheters produced leptomeningeal fibrosis, sometimes with spinal cord compression. Dezocine lactate infusion, in addition to similar leptomeningeal changes, was also associated with severe parenchymal lesions in all cases. The exact cause of this toxicity cannot be specifically assigned; potential contributing factors include catheter-induced reaction, pH of the drug, lactate concentration, osmolality and the pharmacologic agent itself. Leptomeningeal reaction in control dogs limits the value of chronic intrathecal dog models for assessment of spinal drug toxicity.

Analgesics, Opioid↗
PubMed1980

Comparative aspects of the disposition and metabolism of xenobiotics in fish and mammals.

The number of studies in aquatic toxicology has rapidly increased due to the importance of fish as a food source and also because of the increasing awareness of long-term health hazards of aquatic pollution of humans as well as to aquatic flora and fauna. The bioaccumulation and persistence of certain chemicals in fish have been studied for some time but with the characterization of an active hepatic mixed function oxidase system, comparable in many respects to that found in mammals, the role of metabolism in the disposition, toxicity, and persistence of certain chemicals can be studied. The recent observation that rainbow trout and their eggs are very sensitive to aflatoxin B1, a carcinogen that apparently must be activated to a chemically reactive intermediate to exert its effect, has led to the development of fish being considered appropriate animal models for toxicity testing. Since most predictive toxicology in the past has been restricted to nonaquatic species, this review has attempted to describe some of the similarities and dissimilarities between mammals and fish in terms of absorption, distribution, metabolism, and excretion of xenobiotics.

Animals↗
PubMed1991

Product toxicity and cometabolic competitive inhibition modeling of chloroform and trichloroethylene transformation by methanotrophic resting cells.

The rate and capacity for chloroform (CF) and trichloroethylene (TCE) transformation by a mixed methanotrophic culture of resting cells (no exogenous energy source) and formate-fed cells were measured. As reported previously for TCE, formate addition resulted in an increased CF transformation rate (0.35 day-1 for resting cells and 1.5 day-1 for formate-fed cells) and transformation capacity (0.0065 mg of CF per mg of cells for resting cells and 0.015 mg of CF per mg of cells for formate-fed cells), suggesting that depletion of energy stores affects transformation behavior. The observed finite transformation capacity, even with an exogenous energy source, suggests that toxicity was also a factor. CF transformation capacity was significantly lower than that for TCE, suggesting a greater toxicity from CF transformation. The toxicity of CF, TCE, and their transformation products to whole cells was evaluated by comparing the formate oxidation activity of acetylene-treated cells to that of non-acetylene-treated cells with and without prior exposure to CF or TCE. Acetylene arrests the activity of methane monooxygenase in CF and TCE oxidation without halting cell activity toward formate. Significantly diminished formate oxidation by cells exposed to either CR or TCE without acetylene compared with that with acetylene suggests that the solvents themselves were not toxic under the experimental conditions but their transformation products were. The concurrent transformation of CF and TCE by resting cells was measured, and results were compared with predictions from a competitive-inhibition cometabolic transformation model. The reasonable fit between model predictions and experimental observations was supportive of model assumptions.

Binding, Competitive↗
PubMed1999

Structural and functional changes in photosynthetic apparatus of wheat under exposure to sulfur dioxide fumes.

Changes in photosynthesis of wheat (pigment content and chlorophyll fluorescence) have been measured to study effect of gaseous sulfur dioxide on wheat cenosis. Several biochemical and biophysical techniques have been estimated to evaluate their ability for early detection of destructive effect of SO2. A mathematical model of toxic gas absorption in a closed system with plants has been proposed.

Absorption↗
PubMedDate not supplied

Protocol for early detection and evaluation of inhibitory wastewater using combined aerobic respirometric and anaerobic batch techniques.

Faced with the task of treating significant volumes of complex industrial wastewaters, the biological components of municipal wastewater treatment plants are operating under the risk of toxic or inhibitory contaminants from the industrial effluents that may be detrimental to their operation. This might lead to undesirable effluent toxicity and/or result in permit violations. Therefore, there is a need for upset early warning systems that can protect full-scale plants from toxic or inhibitory constituents in the incoming wastewaters. This study focused on the development of a protocol for rapid detection of potentially toxic inhibitory or toxic wastewaters using combined aerobic respirometric and anaerobic batch techniques. Aerobic respirometers equipped with automated data acquisition systems were used as potential early warning devices. The inhibition effect on carbon and nitrogen oxidation was assessed. The degree of inhibition was evaluated as the concentration causing 50% reduction in microbial activity, which was estimated by an inhibition model. Anaerobic toxicity assays were also conducted to evaluate the inhibitory effects of the toxic compounds to anaerobic inocula obtained from a master culture reactor fed with ethanol. The developed protocol for early detection of toxicity was validated using wastewater samples from a biotechnology industry and a food processing industry, and pure chemicals such as furfural and phenol. Varying degrees of sensitivity were observed in the study when different groups of microorganisms, wastewater samples, and chemicals were tested. The comparison of aerobic and anaerobic inhibition suggested the importance of using both aerobic and anaerobic cultures to maximize the necessary sensitivity of the protocol.

Anaerobiosis↗
PubMed1986

Acute high-dose methotrexate neurotoxicity in the rat.

Intravenous high-dose methotrexate chemotherapy may produce acute, subacute, or chronic neurotoxicity in patients with cancer. Acute encephalopathies following high-dose methotrexate treatment are recognized with increasing frequency. This study describes a model of acute high-dose methotrexate neurotoxicity in the rat characterized by a profound dose-dependent depression of cerebral glucose metabolism in association with behavioral and electroencephalographic abnormalities. Alterations in the amino acid profile, similar to those described in cancer patients after high-dose methotrexate treatment, were observed in the absence of biochemical evidence of systemic organ toxicity. This model facilitates the study of the biochemical mechanisms of antifolate neurotoxicity in humans and permits the evaluation of potential therapeutic interventions.

Amino Acids↗
PubMed2003

Estimation of the upper limit of human butyrylcholinesterase dose required for protection against organophosphates toxicity: a mathematically based toxicokinetic model.

Human butyrylcholinesterase (HuBChE) is a drug candidate for protection against organophosphates (OP) intoxication. A mathematically based model was validated and employed to better understand the role of the endogenous HuBChE in detoxification of OPs and to estimate the dose of exogenous HuBChE required for enhancing protection of humans from lethal exposure to OPs. The model addresses the relationship between the HuBChE dose needed to maintain a certain residual activity of human acetylcholinesterase (HuAChE) and the following parameters: (1) level and duration of exposure, (2) bimolecular rate constants of inhibition of HuAChE (kA) and HuBChE (kB) by OPs, and (3) time elapsed from enzyme load. The equation derived for the calculation of HuBChE dose requires the knowledge of kA/kB in human blood and the rate constant of HuBChE elimination. Predictions of HuBChE doses were validated by in vitro experiments and data of published human studies. These predictions highlight two parameters that are likely to decrease the calculated dose: (1) the rapid consumption of the less toxic isomers of OPs in human plasma, and (2) the volume of distribution of HuBChE that appears significantly greater than the volume of plasma. The first part of the analysis of the proposed model was focused on acute bolus exposures and suggests that upper limit doses of 134, 115, and 249 mg/70 kg are sufficient to protect RBC AChE above 30% of baseline activity following a challenge with 1 LD(50) VX, soman, and sarin, respectively. The principles of the validated model should be applicable for advanced predictions of HuBChE dose for protection against continuous exposures to OPs.

Acetylcholinesterase↗
PubMed1995

An insect model for assessing oxidative stress related to arsenic toxicity.

The potential usefulness of an insect model to evaluate oxidative stress induced by environmental pollutants was examined with trivalent arsenic (As3+, NaAsO2) and pentavalent arsenic (As5+, Na2HAsO4) in adult female house flies, Musca domestica, and fourth-instar cabbage loopers, Trichoplusia ni. M. domestica was highly susceptible to both forms of arsenic following 48 h exposure in the drinking water with LC50s of 0.008 and 0.011% w/v for As3+ and As5+, respectively. T. ni larvae were susceptible to dietary As3+ with an LC50 of 0.032% w/w but seem to tolerate As5+ well with an LC50 of 0.794% concentration after 48 h exposure. The minimally acute LC5 dose of both As3+ and As5+ varied considerably but averaged 0.005% for both insects. The potential of both valencies of arsenic for inducing oxidative stress in the insects exposed ad libitum to approximately LC5 levels was assessed. The parameters examined were the alterations of the antioxidant enzyme activities of superoxide dismutase (SOD), catalase (CAT), glutathione transferase (GST), the peroxidase activity of glutathione transferase (GSTPX), and glutathione reductase (GR), and increases in lipid peroxidation and protein oxidation. SOD (1.3-fold), GST (1.6-fold), and GR (1.5-fold) were induced by As3+ in M. domestica but CAT and GSTPX were not affected. As5+ had no effect on M. domestica. In T. ni, the antioxidant enzyme activities were not affected by As3+ except for SOD which was suppressed by 29.4% and GST which was induced by 1.4-fold. As5+ had no effect except the suppression of SOD by 41.2%. Lipid peroxidation and protein oxidation, which represent stronger indices of oxidative stress, were elevated in both insects by up to 2.9-fold. However, based on the antioxidant enzyme response to the arsenic anions, the mode of action of arsenic induced oxidative stress may differ between the two insects. Until this aspect is further clarified, evidence at this time favors the prospect of As3+ as a pro-oxidant, especially for M. domestica.

Animals↗
PubMed2004

Pyridoxine-induced toxicity in rats: a stereological quantification of the sensory neuropathy.

Excess ingestion of pyridoxine (vitamin B6) causes a severe sensory neuropathy in humans. The mechanism of action has not been fully elucidated, and studies of pyridoxine neuropathy in experimental animals have yielded disparate results. Pyridoxine intoxication appears to produce a neuropathy characterized by necrosis of dorsal root ganglion (DRG) sensory neurons and degeneration of peripheral and central sensory projections, with large diameter neurons being particularly affected. The major determinants affecting the severity of the pyridoxine neuropathy appear to be duration and dose of pyridoxine administration, differential neuronal vulnerability, and species susceptibility. The present study used design-based stereological techniques in conjunction with electrophysiological measures to quantify the morphological and physiological changes that occur in the DRG and the distal myelinated axons of the sciatic nerve following pyridoxine intoxication. This combined stereological and electrophysiological method demonstrates a general approach that could be used for assessing the correlation between pathophysiological and functional parameters in animal models of toxic neuropathy.

Animals↗
PubMed2005

Scenario-based simulation of runoff-related pesticide entries into small streams on a landscape level.

The prediction of runoff-related pesticide entry into surface waters on a landscape level usually requires considerable efforts with regard to input data, time, and personnel. Therefore, the need for an easy to use simulation tool with easily accessible input data, for example from already existing public sources, is obvious. In this paper, we present a simulation tool for the simulation of pesticide entry from arable land into adjacent streams. Our aim was to develop a tool applicable on the landscape level using "real world data" from numerous sites and for the simulation of parameter case studies concerning particular parameters at single sites. We used the ratio of exposure to toxicity (REXTOX) model proposed by the OECD, which had been successfully validated in the study area as part of a previous study and which was extended to calculate pesticide concentrations in adjacent streams. We simulated the pesticide entry on the landscape level at 737 sites in small streams situated in the central lowland of Germany with winter wheat, barley, and sugar beat as the main agricultural crops. A sensitivity analysis indicated that the most significant model parameters were the width of the no-application zone and the degree of plant interception. The simulation was carried out for the 15 most frequently detected substances found in the study area using eight different environmental scenarios, covering variation of the width of the no-application zone, climate, and seasonal scenarios. The highest in-stream concentrations were predicted for a scenario using no (0m) buffer zone in conjunction with increased precipitation. According to the predicted concentrations, the risk for the aquatic communities was estimated based on standard toxicity tests and the application of a safety factor. The simulation results are presented both by means of risk maps for the study area showing the simulated pesticide concentration and the resulting ecological risk for numerous sites under varying scenarios and by case study diagrams with focus on the model behavior under the influence of single parameters. Risk maps confirmed the importance of no-application (buffer) zones for the levels of pesticide input. They also indicated the importance of the existing no-application zones for certain compounds and in some cases the need for a further evaluation of these regulations. The simulation tool was implemented as a standard PC software combining the REXTOX model with a geographical information system and can be used on any current personal computer. All input data was taken from public sources of German authorities. With little effort the tool should be applicable for other areas with similar data quality.

Computer Simulation↗
PubMed1995

Combination of immunotherapy with cyclophosphamide/actinomycin D chemotherapy potentiates antileukemic effect and reduces toxicity in a L1210 leukemia model in mice.

The therapeutic effects of the combination of chemotherapy (cyclophosphamide and actinomycin D) and immunotherapy (TNF-alpha and macrophages) were evaluated on L1210 leukemia in mice. When given as single agents, both cyclophosphamide (CY), administered intraperitoneally 2 days after subcutaneous inoculation of leukemic cells, and actinomycin D (Act D), injected intratumorally (i.t.) 4 days following injection of leukemic cells, exerted therapeutic effects and prolonged mice survival. Unexpectedly, combination of CY and Act D did not result in prolongation of mice survival, due mainly to substantial cumulative toxic effects that led to death in several cases. Immunotherapy with TNF-alpha and M phi, injected i.t. on day 4 following inoculation of leukemic cells, did not give significant therapeutic effect, either when used alone or when used in conjunction. However, combination of chemotherapy and immunotherapy, including all four agents, produced a beneficial effect resulting in significant prolongation of the survival of leukemia-bearing mice. This study indicates the potential of appropriate combinations of cytotoxic drugs with immunotherapy against neoplasia.

Animals↗
PubMed1995

Further studies of the in vitro activity of synthetic gliadin peptides in coeliac disease.

Studies of in vitro activity of synthetic peptides derived from the A-gliadin structure were carried out using assays based on cultures of foetal chick intestinal mucosa and on incubation with rat liver lysosomes. The peptide corresponding to residues 11-19, displayed very high activity in the chick intestinal assay, but was only weakly active in the lysosomal assay. Peptide 9-19 was highly active in the chick intestinal assay but was only mildly active in the lysosomal assay. Peptide 8-19 was still appreciably active in both assays. The results on this group of peptides suggest the importance of residues 8-12 to activity and possibly also of a N-terminal glutamine residue. The peptide 213-227, found in a sub-fraction of fraction 9, was only weakly active in both assays, indicating that the PSQQ motif was not solely responsible for toxicity. Thus, as the peptide 208-219 was shown previously to be active in the chick intestinal assay, it is likely that the 208-212 region of this peptide is of prime importance in conferring activity. The results show, for the first time, that a nonapeptide from the N-terminal region of A-gliadin is very active in an in vitro model of toxicity in coeliac disease.

Amino Acid Sequence↗
PubMed1986

[Hyperthermia of malignant brain tumors--development of an interstitial microwave hyperthermia system and study of thermodosimetry and heat toxicity in a canine brain model].

Hyperthermia is a promising important adjunct to conventional treatment of malignant brain tumors and available data suggest a strong biological rationale for its use. Hyperthermia has been shown to sensitize tumors to radiation, particularly radiation delivered at low dose rates typical of brachytherapy. To complement our clinical study of interstitial brachytherapy of malignant brain tumors, a microwave interstitial heating system with data acquisition has been constructed at UCSF. This system was evaluated in a phantom and in a series of non-survival and survival experiments for heating patterns and heat toxicity in 24 adult canine brains. A single 2450 MHz microwave heating antenna and 3 fiberoptic thermometry probes were placed stereotaxically into the frontal white matter of 24 dogs. Temperature measurements were made at 1 mm increments along the antenna length 5 mm from the antenna axis and radially away from the antenna junction. For the survival studies, minimum temperatures 43 degrees C, 44 degrees C, and 45 degrees C were maintained at points 5 mm from the antenna junction for 30 minutes. Hyperthermia-induced tissue damage was measured weekly following the heat treatment using CT. In general, it was easy to maintain a steady temperature state for a long time period. Heating patterns tended to be ellipsoidal, corresponding relatively well with those predicted by the phantom trials. Heat toxicity was examined by sequential quantitative CT scans in chronic trials and correlated with histopathology following sacrifice at 1-16 weeks. Neurological deficits were minimal and were restricted to the first day after treatment.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed2000

A probability model of vector behavior: effects of DDT repellency, irritancy, and toxicity in malaria control.

A probability model of how DDT residues may function within a malaria control program is described. A step-wise organization of endophagic behaviors culminates in a vector acquiring a human blood meal inside the house. Different vector behaviors are described, epidemiologically defined, temporally sequenced, and quantified with field data. Components of vector behavior and the repellent, irritant, and toxic actions of insecticide residues are then assembled into a probability model. The sequence of host-seeking behaviors is used to partition the total impact of sprayed walls according to the three chemical actions. Quantitatively, the combined effect of repellency and irritancy exert the dominant actions of DDT residues in reducing man-vector contact inside of houses. These relationships are demonstrated with published and unpublished data for two separate populations of Anopheles darlingi, for Anopheles gambiae and Anopheles funestus in Tanzania, and Anopheles punctulatus in New Guinea.

Animals↗