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PubMed2006

Cross-species comparative toxicogenomics as an aid to safety assessment.

Cross-species comparative toxicogenomics has the potential for improving the understanding of the different responses of animal models to toxicants at a molecular level. This understanding could then lead to a more accurate extrapolation of the risk posed by these toxicants to humans. Cross-species comparative studies have been carried out at the genomic sequence level and using microarrays to examine changes in global mRNA profiles. However, these studies face considerable bioinformatic challenges in terms of identifying which genes are truly orthologous across species. The resources to analyse such studies, in the context of such orthologues, beg improvement. Finally, the experimental design of such studies needs to be carefully considered to make their results fully interpretable. These issues are discussed, along with the current state-of-the-art cross-species comparative toxicogenomics in this review.

Animals↗
PubMed2006

Cystine/glutamate exchange modulates glutathione supply for neuroprotection from oxidative stress and cell proliferation.

The cystine/glutamate exchanger (xCT) provides intracellular cyst(e)ine for production of glutathione, a major cellular antioxidant. Using xCT overexpression and underexpression, we present evidence that xCT-dependent glutathione production modulates both neuroprotection from oxidative stress and cell proliferation. In embryonic and adult rat brain, xCT protein was enriched at the CSF-brain barrier (i.e., meninges) and also expressed in the cortex, hippocampus, striatum, and cerebellum. To examine the neuroprotective role of xCT, various non-neuronal cell types (astrocytes, meningeal cells, and peripheral fibroblasts) were cocultured with immature cortical neurons and exposed to oxidative glutamate toxicity, a model involving glutathione depletion. Cultured meningeal cells, which naturally maintain high xCT expression, were more neuroprotective than astrocytes. Selective xCT overexpression in astrocytes was sufficient to enhance glutathione synthesis/release and confer potent glutathione-dependent neuroprotection from oxidative stress. Moreover, normally nonprotective fibroblasts could be re-engineered to be neuroprotective with ectopic xCT overexpression indicating that xCT is a key step in the pathway to glutathione synthesis. Conversely, astrocytes and meningeal cells derived from sut/sut mice (xCT loss-of-function mutants) showed greatly reduced proliferation in culture attributable to increased oxidative stress and thiol deficiency, because growth could be rescued by the thiol-donor beta-mercaptoethanol. Strikingly, sut/sut mice developed brain atrophy by early adulthood, exhibiting ventricular enlargement, thinning of the cortex, and shrinkage of the striatum. Our results indicate that xCT can provide neuroprotection by enhancing glutathione export from non-neuronal cells such as astrocytes and meningeal cells. Furthermore, xCT is critical for cell proliferation during development in vitro and possibly in vivo.

Animals↗
PubMed2001

Quantitative structure-activity relationships: comparative inhibition of nitrogen-containing aromatics on germination of Cucumis sativus.

Comparative inhibition effect of selected nitrogen-containing aromatics on germination rate of Cucumis sativus was investigated, and quantitative structure-activity relationships were developed and mechanistically interpreted. Energy of lowest unoccupied orbital was found to successfully model the toxicity of the test chemicals. It was discovered that inhibition of nitrogen-containing aromatics to germination of Cucumis sativus was caused mainly by their in vivo redox reaction.

Aminopyridines↗
PubMed1998

Preclinical oral toxicology in rats of D-002, a natural drug with antiulcer effects.

D-002 is a mixture of higher aliphatic primary alcohol isolated from bees wax (Apis mellifera) with effective antiulcer effects demonstrated in different experimental models. Oral toxicity of D-002 (5-5000 mg/kg) was evaluated in sub-acute (14 days), subchronic (90 days) and chronic (1 year) studies in Sprague-Dawley rats from both sexes. There was no treatment-related toxicity. Thus, effects on body weight, food consumption, clinical observations, blood parameters, organ weight ratios and histopathological findings were similar in control and treated groups. These short and long-term studies support a wide safety margin for this product.

Administration, Oral↗
PubMed1995

Review of modified hemoglobin research at Letterman: attempts to delineate the toxicity of cell-free tetrameric hemoglobin.

In the final two years, June 1991 to June 1993, of the Letterman Army Institute of Research, a variety of cell, tissue, organ, and animal systems were used to explore the toxicities of model hemoglobin (Hb) solutions produced in the sterile Hb production facility. Human mononuclear cells release TNF alpha and Il-8 when exposed to chromatographically purified human Hb (HbA0). Mixed cultures of fetal mouse neurons and glial cells exhibit neuronal death with exposure to HbA0 in a dose and time dependent manner while the glial cells are not injured. Isolated perfused rabbit hearts were used to explore the reversibility of coronary vasoconstriction after Hb and cyanomet-Hb administration, and deferoxamine was shown to partially protect that reversibility. In rabbits HbA0 and human Hb cross-linked with bis(3,5-dibromosalicyl) fumarate (alpha alpha Hb) caused hypertension and pulmonary arteritis. In swine, HbA0 and alpha alpha Hb caused systemic and pulmonary hypertension and a doubling of the vascular resistance that was equivalent to that seen with inhibition of nitric oxide synthesis. Elevations of creatine kinase and lactic dehydrogenase activity were observed after Hbs were infused, but not after blockade of nitric oxide synthesis. Acute renal failure seen after administration HbA0, did not appear after alpha alpha Hb. Infusion of cyanomet-alpha alpha Hb did not cause the increased vascular resistance seen after alpha alpha Hb. The infusion of 1-arginine or nitroglycerine with alpha alpha Hb did not prevent the increased vascular resistance and decreased cardiac output or allow the increased oxygen carrying capacity provided by Hb in the plasma from translating into improved oxygen delivery or improved oxygen consumption.

Animals↗
PubMedDate not supplied

[Hepatoprotective effect of lipophen--a novel natural combined phospholipid preparation].

Studied in vitro, lipophen (in contrast to essentiale) did not separate the oxidation and phosphorylation processes in intact mitochondria. The antioxidant effect of lipophen with respect to enzymatic or ascorbate-dependent lipid peroxidation in intact microsomes from rat liver was higher by two-three orders of magnitude as compared to the effect of essentiale. In rats with a toxic hepatitis model induced by ethanol, lipophen restored the activity of mitochondria on a level characteristic of intact animals. In the case of CCl4-induced hepatitis, lipophen significantly increased the hydroxylase activity.

Acute Disease↗
PubMed2001

Altered metabolite concentrations with amiodarone generic substitution cannot be observed without monitoring.

The use of amiodarone has grown rapidly, resulting in the marketing of several generic formulations. The adequacy of the testing used to approve these formulations as bioequivalent has been questioned, and mounting clinical evidence suggests that in some patients, substitution with generic amiodarone can cause serious problems. The effects of switching amiodarone formulations may take weeks to develop, leaving the relationship between the events unrecognized. In animal models, the toxicity of desethylamiodarone, an active metabolite partly formed during amiodarone absorption, is greater than that of its parent compound. High metabolite to amiodarone ratios have been associated with clinical toxicity. Because measuring serum amiodarone and metabolite is not standard clinical practice, aberrations after switching formulations will be missed. Major changes in metabolite concentrations were documented in four patients switched to a generic formulation, suggesting that the tests used for regulatory approval failed to identify the cumulative effects of differing excipients on amiodarone metabolism during absorption. Physicians should monitor patients for several months after a switch in amiodarone formulation is made. Regulatory criteria for bioequivalence of amiodarone need to be reconsidered.

Adult↗
PubMed2001

Organochlorine pesticides and chlorinated hydrocarbon solvents in the blood of chemically sensitive patients [corrected]. A statistical comparison with therapeutic medication and natural hormones.

The blood levels of organochlorine pesticides and chlorinated hydrocarbon solvents were measured in 200 and 114 chemically sensitive patients respectively, and compared with blood concentrations of standard medication (non- chlorinated substances. Clonidine, Haloperidol) of comparable toxicity after therapeutically effective dosage, and with reference levels of highly potent chemicals in the blood such as hormones. It was shown that the average blood levels of the most toxic environmental pollutants are comparable with the therapeutic steady state average blood levels of medications which have similar toxicities in the animal model. In addition the toxicity levels of xenoestrogens are at least an order of magnitude higher than normal plasma estrogen or progesterone levels. These findings suggest the possibility of additive or synergistic effects of these chlorinated compounds and the aforementioned medications. Also, these findings suggest the possibility of hormone deregulation from exposure to the aforementioned toxic chlorinated compounds.

Adolescent↗
PubMedDate not supplied

[Hepatoprotective properties of liquid extract of Rhodiola rosea].

The effect of a liquid extract from Rhodiola rosea on the functional state of rat liver with experimental toxic hepatitis was studied. The extract produces a hepatoprotective effect, as manifested by normalized activity of aspartate aminotransferase and alkaline phosphatase, normalized content of medium-molecular-weight peptides, urea, and bilirubin, and reduced activity of alanine aminotransferase and glutathione-S-transferase in the blood plasma of rats with the toxic hepatitis model.

Animals↗
PubMedDate not supplied

[Interaction of the toxic plant protein--ricin, with model membranes. A fluorescence method of study].

The fluorescence method has been used to investigate ricin and its isolated subunits interaction with some model membranes. Three liposome types were used as a model of biological membrane: 1) liposomes constructed from lecithin and cholesterol (9:1, M:M) 2) from ganglioside receptors GM1 and 3) from the mixture of GM1, lecithin and cholesterol (1:9:1). Interaction of the protein with liposome evokes changes in the parameters of both intrinsic protein fluorescence and fluorescence of the covalently bound dansyl. Binding constants were calculated from a decrease of the intrinsic fluorescence intensity as well as from the changes in the dansyl rotation anisotropy. Measurements were carried out at neutral and acidic pH. There was good correlation of the results obtained by different methods. It was shown that association constants were different for intact ricin and its subunits. The constants also depend on liposome composition and pH of the solution. The present study has demonstrated that interaction of ricin with liposome is accounted for not only by receptor centers but also by other hydrophobic regions of ricin that are inaccessible in the native toxin and may represent the region of the subunits interaction.

Cholesterol↗
PubMed2006

[Effect of 1, 2-dichloroethane on blood brain barrier].

OBJECTIVE: To investigate the effect of 1, 2-dichloroethane (1, 2-DCE) on blood brain barrier. METHODS: Acute toxic encephalopathy model was copied with the consecutive static inhalation of 1, 2-DCE. The water content of brain tissue was measured, and the blood brain barrier permeability was detected with lanthanum nitrate. The brain microvascular endothelial cells and neuroglial cells were cultured in vitro, which were administrated with 1, 2-DCE. The cell morphologic structures were observed under light microscope and electron microscope. RESULTS: (1) The extracellular edema was most found in the cerebral tissue and the leakage of lanthanum particles through the barrier were found with the lanthanum tracking method. (2) The water content in cerebral cortex in the moderate and high dose groups was significantly higher than that in the control group and became severer with the increases of the intoxicated time. The water content in cerebral medulla was significantly increased only at 6 hours after the intoxication. (3) The normal morphological structure of brain microvascular endothelial cells and neuroglial cells could be injured by 1, 2-DCE, and the injury to neuroglial cells caused by 1, 2-DCE occurred earlier and severer than that to brain microvascular endothelial cells. CONCLUSION: 1, 2-DCE can damage blood brain barrier and induce cerebral edema.

Administration, Inhalation↗
PubMed2006

Preclinical pharmacokinetic, biodistribution, toxicology, and dosimetry studies of 111In-DTPA-human epidermal growth factor: an auger electron-emitting radiotherapeutic agent for epidermal growth factor receptor-positive breast cancer.

UNLABELLED: Our objective was to evaluate the pharmacokinetics, normal tissue distribution, radiation dosimetry, and toxicology of human epidermal growth factor (hEGF) labeled with (111)In ((111)In-diethylenetriaminepentaacetic acid [DTPA]-hEGF) in mice and rabbits. METHODS: (111)In-DTPA-hEGF (3.6 MBq; 1.3 or 13 microg) was administered intravenously to BALB/c mice. The blood concentration-time data were fitted to a 3-compartment model. Acute toxicity was studied with female BALB/c mice at 42 times the maximum planned human dose (MBq/kg) or with New Zealand White rabbits at 1 times the maximum planned human dose (MBq/kg) for a phase I clinical trial. Toxicity was evaluated by monitoring body weight, by determination of hematology and clinical biochemistry parameters, and by morphologic examination of tissues. Radiation dosimetry projections in humans were estimated on the basis of the residence times in mice by use of the OLINDA version 1.0 computer program. RESULTS: The largest amounts of radioactivity were taken up by the liver (41.3 +/- 7.8 [mean +/- SD] percentage injected dose [%ID] at 1 h after injection and decreasing to 4.9 +/- 0.3 %ID at 72 h after injection) and kidneys (18.6 +/- 0.8 %ID at 1 h and decreasing to 4.5 +/- 0.2 %ID at 72 h after injection). (111)In-DTPA-hEGF was cleared rapidly from the blood, with a half-life at alpha-phase of 2.7-6.2 min and a half-life at beta-phase of 24.0-36.3 min. The half-life of the long terminal phase could not be accurately determined. The volume of distribution of the central compartment was 340-375 mL/kg, and the volume of distribution at steady state was 430-685 mL/kg. There was no significant difference in the ratio of body weight at 15 d to pretreatment weight for mice administered (111)In-DTPA-hEGF (1.02 +/- 0.01) and mice administered unlabeled DTPA-hEGF (1.01 +/- 0.01). Erythrocyte, leukocyte, and platelet counts and serum alanine aminotransferase and creatinine levels remained in the normal ranges. No morphologic changes were observed by light microscopy in any of 19 tissues sampled. Minor morphologic changes in the liver were observed by electron microscopy. The projected whole-body dose in humans was 0.19 mSv.MBq(-1). The projected doses to the liver, kidneys, and lower large intestine were 0.76, 1.82, and 1.12 mSv.MBq(-1), respectively. CONCLUSION: (111)In-DTPA-hEGF was safely administered to mice and rabbits at multiples of the maximum dose planned for a phase I trial in breast cancer patients.

Animals↗
PubMed1991

Methanol-induced visual toxicity in the rat.

Human methanol poisoning is characterized by formic acidemia, metabolic acidosis and blindness or serious visual impairment. Nonprimate species are ordinarily resistant to the accumulation of formate and the associated metabolic and visual toxicity. A nonprimate model of methanol-induced visual toxicity was developed using rats treated with subanesthetic concentrations of nitrous oxide to inhibit the oxidation of methanol's toxic metabolite, formic acid. Methanol-intoxicated rats developed formic acidemia, metabolic acidosis and visual toxicity within 36 hr of methanol administration analogous to the human methanol poisoning syndrome. Visual dysfunction was measured as reductions in the flash-evoked cortical potential and electroretinogram, which occurred coincident with blood formate accumulation. Alterations in the electroretinogram occurred at formate concentrations lower than those associated with other visual changes and provide functional evidence of direct retinal toxicity in methanol poisoning.

Acidosis↗
PubMedDate not supplied

[The liver-protective properties of D-glucosamine].

The antioxidant and membrane-stabilizing activities of D-glucosamine were studied on two models of toxic liver damage. When administered in a dose of 50 mg/kg, D-glucosamine was found to prevent the development of the hepatocyte cytolysis syndrome, to normalize the cholate- and glycogen-synthetic functions of the liver. D-glucosamine exhibited a significant anabolic effect that also supplemented its hepatoprotective activity.

Animals↗
PubMed1990

Evidence that high mannose glycopeptides are able to functionally interact with recombinant tumor necrosis factor and recombinant interleukin 1.

Both recombinant tumor necrosis factor (rTNF) and recombinant interleukin 1 (rIL-1) are able to mediate vascular collapse and death in a previously described murine model, using galactosamine to enhance the toxicity of these cytokines. Unexpectedly, both acid-treated tumor necrosis factor (TNF) and a site-specifically mutagenized form of interleukin 1 (IL-1) (His-30----Arg-30), which fails to bind to the IL-1 receptor, retain full in vivo toxicity in this model of TNF- and IL-1-mediated shock. Previous studies have shown that rTNF and rIL-1 exhibit two functionally distinct binding regions. Both cytokines bind to their respective cell surface receptors and they also express lectin like binding specificity (Muchmore and Decker, J. Biol. Chem., 261: 13404-13407, 1986; Muchmore and Decker, J. Immunol., 138: 2541-2546, 1987) for defined oligosaccharides. The specificity of these two types of interactions is quite different. Cell surface receptors for IL-1 and TNF demonstrate essentially no cross-reactivity, whereas, in the case of carbohydrate binding, competition studies reveal an almost identical carbohydrate specificity for the structure Man5(6)GlcNAc2-Asn. Man5(6)GlcNAc2-Asn binding is either unaffected or actually enhanced by either acid treatment of rTNF or mutation at His-30 for rIL-1. Both deoxymannojirimycin and swainsonine, inhibitors of glycoprotein processing, raise intracellular levels of Man5-9GlcNAc2 and enhance the in vitro biological activity of both rTNF and rIL-1. Conversely, castanosperimine, a glucosidase I inhibitor which blocks the synthesis of mature high mannose structures, inhibits the biological activity of IL-1. These observations support the hypothesis that some effects of IL-1 and TNF may involve interaction with high mannose-substituted glycoproteins.

Animals↗
PubMed1989

Induction of TNF in vitro as a model for the identification of toxic malaria antigens.

Tumour necrosis factor (TNF) has been implicated as a mediator of toxicity in a number of infectious diseases, including malaria. We have shown that human and rodent blood-stage parasites liberate heat-stable soluble antigens that induce the release of TNF by activated macrophages in vitro and in vivo, and are toxic to mice made hypersensitive to TNF by D-galactosamine. These antigens induce T-independent antibodies which specifically block their ability, but not that of bacterial lipopolysaccharide, to cause the secretion of TNF. Cytokine release in vitro may be a useful strategy for identifying potentially toxic molecules of infectious organisms and for investigating the nature of antibodies that can protect the host against their damaging effects.

Animals↗
PubMed1989

The role of liposomal amphotericin B in the treatment of systemic fungal infections.

Amphotericin B remains the treatment of choice for systemic fungal infections, but amphotericin B is toxic and is often not effective in treating disseminated infections. Liposome intercalation of amphotericin B reduces the toxicity associated with amphotericin B and targets reticuloendothelial tissues most heavily involved in fungal infections. The targeted delivery and reduced toxicity of liposomal amphotericin B improves the therapeutic index of amphotericin B. Although liposomes have been shown to effectively treat a variety of experimental and human fungal infections, the optimal composition of liposomal amphotericin has not been established. Vesicle type, lipid content, size, and conditions of storage markedly affect toxicity, therapeutic efficacy, and tissue distribution. In vitro studies have been poor predictors of in vivo efficacy and toxicity. Animal models can be used to evaluate in vivo the optimal liposome preparation. Liposomal amphotericin B appears to be an improved means of amphotericin B delivery and may improve the treatment of patients with systemic fungal infections.

Amphotericin B↗