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PubMed1989

Epidemiology and mechanistic basis of analgesic-associated nephropathy.

End-stage renal failure (ESRF) due to analgesic nephropathy is still a common clinical condition in several countries, but the prevalence in dialysis patients shows large geographical differences. The frequency of ESRF of unknown aetiology is the inverse of that linked to analgesic abuse, and data suggest that the occurrence of analgesic nephropathy may be underestimated. The study of analgesic nephropathy is difficult because the earliest damage to the kidney is a renal papillary necrosis (RPN), which cannot easily be diagnosed. Continued analgesic abuse generally leads to a progressive secondary cortical degeneration which is easier to diagnose. If analgesic abuse is stopped at an early enough stage in nephropathy, clinical symptoms stabilize or improve, and ESRF may be averted. A high incidence of upper urothelial carcinoma (UUC) is also observed in individuals with a history of analgesic abuse, but it is still not clear if the two have a related pathogenesis. Study of the mechanism of RPN in animals administered analgesics and nonsteroidal antiinflammatory drugs (NSAID) has been difficult owing to their extrarenal toxicity. Several model compounds cause identical clinical changes and have as their selective target the renal medullary interstitial cells; subsequently, other changes (including cortical and glomerular degeneration) develop as a secondary cascade. A number of mechanisms have been proposed to explain RPN (e.g., counter-current concentrating mechanism, ischaemic injury, altered prostaglandin metabolism, immunological changes), but peroxidative metabolism of papillotoxic chemicals within the interstitial cells seems to be the most likely cause. Analgesic abuse is a costly socioeconomic condition for which there is currently no clinical treatment. If it is diagnosed early enough, severe renal degeneration can be prevented. Additional epidemiological information is needed to establish the causative role of analgesics and other chemicals, in order to determine the relative risk of each. Additional animal experiments are needed in order to clarify the molecular pathogenesis of RPN and UUC, to differentiate the stages in progression to ESRF and to develop more sensitive and selective diagnostic criteria.

Analgesics↗
PubMed1987

Xenobiotic biotransformation in livers and lungs of adult black-tailed deer: comparison with domestic goat and sheep.

1. The capacity of liver and lung tissue of black-tailed dear (Odocoileus hemionus columbianus) to biotransform xenobiotics was compared in vitro to the domestic sheep and goat. Donor animals were all females of varying ages. Tissues from the black-tailed deer were collected in the wild. A variety of biotransformation enzymes were measured in both microsomal and cytosolic fractions. 2. Deer liver was lower in total cytochrome P450 concentration, but mono-oxygenase activities were greater compared to sheep and goat. The opposite was true for the lung. 3. Epoxide hydrolase activities were significantly different in deer vs sheep and goat. 4. In general, both hepatic and pulmonary activities were more similar between sheep and goat than either species compared to the deer, however, the magnitude of the hepatic differences did not exceed 5-fold. 5. Based on these limited results, there is no reason to discredit the sheep or goat as a toxicity testing model for deer.

Animals↗
PubMed2005

Sexual dimorphism in urinary metabolite profiles of Han Wistar rats revealed by nuclear-magnetic-resonance-based metabonomics.

Gender-dependent metabolic variation in Han Wistar rats (n=25 male and n=25 female) was investigated using (1)H nuclear magnetic resonance (NMR) spectroscopy of urine coupled with chemometric methods. Statistically discriminatory regions of the spectra for male and female rats were identified and biomarker characterization was achieved by the further application of solid-phase extraction chromatography with NMR detection and high-performance liquid chromatography mass spectrometry. A novel discriminating molecule was identified as the sulfate conjugate of m-hydroxyphenylpropionic acid, which was excreted in higher concentrations by male rats. Other gender-related metabolite differences in the urine profiles included higher levels of trimethylamine-N-oxide, N,N'-dimethylglycine, m-hydroxyphenylpropionic acid, N-acetylglycoprotein, and cholate in samples from female animals. These studies emphasize the utility of multicomponent metabolic profiling for investigating physiological and genetic variation in experimental animals that may be of relevance to their use as models of toxicity and disease.

Animals↗
PubMed2006

Chronic, sublethal nickel acclimation alters the diffusive properties of renal brush border membrane vesicles (BBMVs) prepared from the freshwater rainbow trout.

Brush border membrane vesicles (BBMVs) were prepared from the kidneys of rainbow trout exposed acutely (72 h; 13,380 microg Ni L(-1)), chronically (11 months; 289 microg Ni L(-1)), or chronically and acutely, to waterborne nickel (Ni). Uptake of 63Ni into renal BBMVs was temperature-dependent and fitted a two component kinetic model composed of a saturable, Michaelis-Menten component prominent at lower Ni concentrations, and a moderate linear diffusive component apparent at higher Ni concentrations. Chronic Ni exposure reduced the permeability of the BBM to Ni, evidenced by a significantly reduced slope of the linear diffusive component of BBMV uptake. Efflux of Ni from 63Ni-loaded renal BBMVs was not significantly altered by acute Ni challenge. Both Ca2+ and Mg2+ inhibited uptake of Ni into renal BBMVs when present at a molar ratio to Ni of 1000:1. Mg2+-induced inhibition, however, was concentration-dependent and significant in BBMVs prepared from chronically Ni-acclimated fish at far lower molar ratios of 100 and 10 to 1. The data suggest that subtle, long-term modulation of membrane structure and function in the rainbow trout may be a compensatory response to chronic waterborne Ni exposure. Additionally, the data challenge the assumptions of constancy of the physiological parameters underlying physiologically based approaches to modeling metal toxicity. Such approaches are currently employed to derive water quality criteria for some metals.

Acclimatization↗
PubMed2003

In vitro cytoprotective activity of squalene on a bone marrow versus neuroblastoma model of cisplatin-induced toxicity. implications in cancer chemotherapy.

The development of a non-toxic selective cytoprotective agent that preferentially protects normal tissues from chemotherapy toxicity, without protecting malignant tissues, is a major challenge in cancer chemotherapy research. The available cytoprotective agents are either toxic or lack selective cytoprotective activity. Here, we report the in vitro selective cytoprotective activity of squalene, an isoprenoid molecule with antioxidant properties. Normal human bone marrow (BM) derived colony-forming unit (CFU) growth was increased by squalene in a dose-dependent manner. Squalene (12.5-25 microM) treatment significantly protected the CFUs from cisplatin-induced toxicity; the protective effect was equivalent to reduced glutathione (GSH), a known cytoprotective agent. Squalene also increased the long-term survival of cisplatin-treated 4-week-old CFUs. Cisplatin-induced apoptosis of CFUs as measured by the TUNEL assay was reduced by squalene. To examine the squalene-induced protection of tumours, several neuroblastoma cell lines, including five MYCN-amplified cell lines, were grown in monolayers, as well as in anchorage-independent cultures, in the presence of squalene and cisplatin. Squalene did not protect the neuroblastoma (NBL) cell lines from cisplatin-induced toxicity. In addition, squalene did not protect the NBL cells from carboplatin, cyclophosphamide, etoposide and doxorubicin-induced toxicity. In conclusion, our results suggest that squalene has a selective in vitro cytoprotective effect on BM-derived haematopoietic stem cells that is equipotent to GSH.

Antineoplastic Agents↗
PubMed2006

Selection of new chemical entities with decreased potential for adverse drug reactions.

Adverse drug reactions, such as hepatotoxicity, blood dyscrasias and hypersensitivity are a major obstacle for the use and the development of new medicines. Many forms of organ-directed toxicity can arise from the bioactivation of drugs to so-called chemically reactive metabolites, which can modify tissue macromolecules. It is well established that the toxicities of model hepatotoxins, such as acetaminophen, furosemide, bromobenzene and methapyrilene can be correlated with the generation of chemically reactive metabolites, which can be detected by measurement of the irreversible binding of radiolabelled material to hepatic protein and/or the detection of stable phase II metabolites such as glutathione conjugates. The basic chemistry of the reaction of such metabolites with model nucleophiles is relatively well understood. A major challenge is to define how certain reactive intermediates may chemically modify critical proteins and how modification of specific amino acids may alter protein function which in turn may affect cell signalling, regulation, defence, function and viability. This in turn will determine whether or not bioactivation will result in a particular form of drug-induced injury. It is now clear that even relatively simple reactive intermediates can react in a discriminative manner with particular cellular proteins and even with specific amino acids within those proteins. Therefore both non-covalent, as well as covalent bonds will be important determinants of the target protein for a particular reactive metabolite. Mammalian cells have evolved numerous defence systems against reactive intermediates. Sensitive redox proteins such as Nrf-2 recognize oxidative stress and electrophilic agents. This is achieved by chemical modification of cysteine groups within keap-1, which normally forms an inactive heterodimer with Nrf-2. Modification of keap-1 releases Nrf-2 that translocates to the nucleus and effects gene transcription of a number of genes involved in the detoxication of chemically reactive metabolites. Diminution of protein function can occur by either covalent modification of nucleophilic amino acids (e.g. cysteine, lysine, histidine etc.) or oxidation of thiols, which can be reversible or irreversible. In the case of acetaminophen, more than 30 target proteins have been identified and for several of them, corresponding alterations in protein function have been defined in the context of tissue necrosis. Alternatively, protein modification may induce signalling systems which initiate cell death, an immune response or to an altered tissue genotype.

Acetaminophen↗
PubMed2006

Rotigotine treatment partially protects from MPTP toxicity in a progressive macaque model of Parkinson's disease.

Clinical DA agonist monotherapy trials, which used in vivo imaging of the DA transporter (DAT) to assess the rate of progression of nigrostriatal degeneration, have failed to demonstrate consistent evidence for neuroprotection. The present study aims at reconciling these experimental and clinical data by testing the protective property of the continuously delivered D3/D2/D1 dopamine receptor agonist rotigotine. Using a progressive 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-lesioned (MPTP) macaque model that mimics the progression of Parkinson's disease in vivo ([99mTc]-TRODAT-1 single photon emission computed tomography (SPECT)) and ex vivo ([125I]-nortropane DAT labelling) endpoints were evaluated. After 38 days of treatment followed by two weeks of washout, rotigotine-treated animals were significantly less parkinsonian than the vehicle-treated ones. Such behavioural difference is the consequence of a partial protection of the DA terminals as could be confirmed by ex vivo DAT labelling. However, the protection of nerve terminals was not detected using SPECT. The data suggest that rotigotine exerts partial protection but that conventional imaging would not be able to identify such protection.

Animals↗
PubMed2004

Leucine toxicity in a neuronal cell model with inhibited branched chain amino acid catabolism.

Individuals with the inborn error of metabolism, maple syrup urine disease (MSUD), are identified by newborn screening programs and treated with protein-modified diets that allow near normal growth and development. However, regardless of cause, a protein insult leads to metabolic decompensation, resulting in brain cell damage. The mechanism responsible for the damage is not well characterized due, in part, to the lack of an appropriate experimental model system with impaired branched chain alpha-ketoacid dehydrogenase (BCKD) activity. Here, we describe the construction of a rat pheochromocytoma cell (PC12) model harboring a doxycycline-controlled BCKD-kinase transgene. When BCKD-kinase is over-expressed in these cells, the endogenous BCKD activity is decreased, blocking branched chain amino acid (BCAA) catabolism. In cells over-expressing BCKD-kinase, addition of 25 mM leucine to the medium results in cell death. This experimental cell model accurately mimics the neuronal dysfunction in maple syrup urine disease and should facilitate further understanding of the pathophysiology of this disease and neuronal cell branched chain amino acid metabolism in general.

3-Methyl-2-Oxobutanoate Dehydrogenase (Lipoamide)↗
PubMed2006

5-HT1A receptor agonist-mediated protection from MPTP toxicity in mouse and macaque models of Parkinson's disease.

Excitotoxicity-mediated cell death is involved in Parkinson's disease (PD). 5-HT1A receptor agonists can protect from such mechanisms. The current study demonstrates that the 5-HT1A agonists BAY 639044 and repinotan have neuroprotective effects in a subacute 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of PD. In addition, we also show that both compounds delay the appearance of parkinsonian motor abnormalities in a MPTP monkey model that recapitulates the progressive nature of PD. Thus, BAY 639044 or repinotan treatment was initiated when there was 30% neuronal death in the substantia nigra pars compacta, and nerve terminal loss in the striatum was 40%, i.e., compatible with the clinical situation where early symptomatic patients would receive such a treatment. The delay in appearance of parkinsonian motor abnormalities is a consequence of partial neuroprotection of nigrostriatal dopamine neurons, both at neuronal and terminal levels as shown for BAY 639044. These results suggest that 5-HT1A agonists, such as BAY 639044, may protect from neurodegeneration and delay the worsening of motor symptoms in Parkinson patients.

Animals↗
PubMed2006

Toxicophores: investigations in drug safety.

Adverse drug reactions, such as hepatotoxicity, blood dyscrasias and hypersensitivity are a major obstacle for the use and the development of new medicines. Many forms of organ-directed toxicity can arise from the bioactivation of drugs to the so-called chemically reactive metabolites, which can modify tissue macromolecules. It is well established that the toxicities of model hepatotoxins, such as acetaminophen, furosemide, bromobenzene and methapyrilene can be correlated with the generation of chemically reactive metabolites, which can be detected by measurement of the irreversible binding of radiolabelled material to hepatic protein and/or the detection of stable phase II metabolites such as glutathione conjugates. The basic chemistry of the reaction of such metabolites with model nucleophiles is relatively well understood. A major challenge is to define how certain reactive intermediates may chemically modify critical proteins and how modification of specific amino acids may alter protein function which in turn may affect cell signalling, regulation, defence, function and viability. This in turn will determine whether or not bioactivation will result in a particular form of drug-induced injury. It is now clear that even relatively simple reactive intermediates can react in a discriminative manner with particular cellular proteins and even with specific amino acids within those proteins. Therefore, both non-covalent, as well as covalent bonds will be important determinants of the target protein for a particular reactive metabolite. Mammalian cells have evolved numerous defence systems against reactive intermediates. Sensitive redox proteins such as Nrf-2 recognise oxidative stress and electrophilic agents, through oxidation or covalent modification of thiol groups. Defence genes, such as epoxide hydrolase and glutamate cysteine ligase then become up-regulated in an attempt to reduce the oxidising environment. However, whether the liver receives mild or severe injury depends upon extra-cellular signalling processes between the hepatocytes and non-parenchymal cells, particularly kupffer and natural killer cells (NK/NK T cells). Determination of the nature and downstream effect of these extra-cellular signalling processes is critical in order to design better predictive hepatotoxicity screens. More importantly, to understand and manipulate these signalling processes will aid in the design of safer therapeutic agents, but also contribute to the clinical management of liver disease.

Animals↗
PubMed2001

An in vitro model for evaluation of vaporous toxicity of trichloroethylene and tetrachloroethylene to CHO-K1 cells.

Toxicokinetics of trichloroethylene (TCE) and tetrachloroethylene (PER) in culture medium and their toxicity to CHO-K1 cells were investigated by employing an in vitro vapor exposure system. Cells were cultured in a 60 mm petri dish with a 25 mm glass dish glued in the central area. TCE or PER was added to the central glass dish so that it would evaporate and dissolve in the surrounding medium in which cells were growing. The results showed that the concentration of TCE or PER in medium increased significantly within 20 min and then decreased very rapidly with time. After a 24 h incubation, the residual of TCE or PER in the medium was very low, but was displayed in a dose-dependent manner. Treatment of cells with either TCE or PER resulted in a dose- and time-dependent inhibition of cell growth. A significantly increase in the frequency of micronuclei (MN) was also observed with either TCE or PER treatment. Low doses of TCE (5-20 microl) or PER (1-5 microl) significantly enhanced the intracellular glutathione (GSH) level. However, the level of GSH rapidly decreased with higher doses of TCE (40-80 microl) or PER (10-20 microl). Depletion of cellular GSH showed no effect on the sensitivity of cells to TCE or PER treatment. GSH-conjugation has been proposed as an activation mechanism to account for the nephrotoxicity of TCE and PER, however the toxicity of TCE and PER to CHO-K1 cells is probably mediated through a distinct mechanism.

Animals↗
PubMed1991

Uranium inhibits bone formation in physiologic alveolar bone modeling and remodeling.

The toxic effect of uranium (U) on bone modeling and remodeling was studied by performing histomorphometric measurements in the periodontal cortical bone of rats. Two different single intraperitoneal doses of uranyl nitrate (238U) were administered to two sets of rats respectively (2 and 0.8 mg/kg body wt). Rats treated with the first dose were killed 14 days postinjection (PI) and those treated with the second were killed 14, 30, and 60 days PI. The results revealed a decrease in bone formation in rats treated with uranium. On the remodeling side the decrease in bone formation was coupled to an increase in bone resorption on the 14th day PI. On the modeling side no bone resorption was observed and the decrease in bone formation was linked to an increase in resting bone zones. Bone formation depression as a key event in U intoxication is stressed.

Animals↗
PubMed1989

On the dynamics of a toxicant-individual system.

The dynamics of a toxicant-individual model where the individual is represented by von Bertalanffy dynamics and the uptake model component is one developed by Barber, Suarez & Lassiter is discussed. A sufficient condition for the death of an individual subjected to chemical stress is found. Another possible behavior of the system is an oscillatory mode of individual size and internal chemical concentration determined by a limit cycle. These fluctuations are a consequence of formulations of growth, maintenance, and the dose-response functions in the model system.

Animals↗
PubMed2003

Integrative assessment of marine pollution in Galician estuaries using sediment chemistry, mussel bioaccumulation, and embryo-larval toxicity bioassays.

An integrative assessment of environmental quality was carried out in selected sites along the Galician coast (NW Iberian Peninsula) combining analytical chemistry of seawater and sediments, bioaccumulation in the marine mussel, and embryo-larval sediment toxicity bioassays, in order to link biological and chemical criteria for the assessment of coastal pollution. Maximum values of Hg and Cu in seawater, sediment and mussels, were found in the inner part of Ria of Pontevedra, while maximum levels of organics (polychlorinated biphenyls, hexachlorobenzene and aldrin) were found in mussels from A Coruña. Outstanding values of Cu, Pb and Zn have been found in seawater and sediment from a single site, P3, which also was the most toxic in the embryo-larval bioassays performed with four different phyla of marine organisms: mollusks, echinoderms, arthropods and chordates. Sediment quality effects range-median values provided a valuable reference to predict biological effects from sediment chemistry data, while effects range-low values were too conservative. Sediment toxicity could also be predicted by using a toxic-unit model based on published EC50 values for trace metals and mobilization factors independently obtained from measurements of metal contents in sediments and their elutriates. When chemical and toxicological data are independently used to arrange sampling sites by using non-metric multidimensional scaling, a remarkable degree of concordance between both types of configurations could be observed.

Animals↗
PubMed2006

Developmental neurotoxicity of industrial chemicals.

Neurodevelopmental disorders such as autism, attention deficit disorder, mental retardation, and cerebral palsy are common, costly, and can cause lifelong disability. Their causes are mostly unknown. A few industrial chemicals (eg, lead, methylmercury, polychlorinated biphenyls [PCBs], arsenic, and toluene) are recognised causes of neurodevelopmental disorders and subclinical brain dysfunction. Exposure to these chemicals during early fetal development can cause brain injury at doses much lower than those affecting adult brain function. Recognition of these risks has led to evidence-based programmes of prevention, such as elimination of lead additives in petrol. Although these prevention campaigns are highly successful, most were initiated only after substantial delays. Another 200 chemicals are known to cause clinical neurotoxic effects in adults. Despite an absence of systematic testing, many additional chemicals have been shown to be neurotoxic in laboratory models. The toxic effects of such chemicals in the developing human brain are not known and they are not regulated to protect children. The two main impediments to prevention of neurodevelopmental deficits of chemical origin are the great gaps in testing chemicals for developmental neurotoxicity and the high level of proof required for regulation. New, precautionary approaches that recognise the unique vulnerability of the developing brain are needed for testing and control of chemicals.

Adolescent↗
PubMed2003

Fish tolerance to organophosphate-induced oxidative stress is dependent on the glutathione metabolism and enhanced by N-acetylcysteine.

Dichlorvos (2,2-dichlorovinyl dimethyl phosphate, DDVP) is an organophosphorus (OP) insecticide and acaricide extensively used to treat external parasitic infections of farmed fish. In previous studies we have demonstrated the importance of the glutathione (GSH) metabolism in the resistance of the European eel (Anguilla anguilla L.) to thiocarbamate herbicides. The present work studied the effects of the antioxidant and glutathione pro-drug N-acetyl-L-cysteine (NAC) on the survival of a natural population of A. anguilla exposed to a lethal concentration of dichlorvos, focusing on the glutathione metabolism and the enzyme activities of acetylcholinesterase (AChE) and caspase-3 as biomarkers of neurotoxicity and induction of apoptosis, respectively. Fish pre-treated with NAC (1 mmol kg(-1), i.p.) and exposed to 1.5 mg l(-1) (the 96-h LC85) of dichlorvos for 96 h in a static-renewal system achieved an increase of the GSH content, GSH/GSSG ratio, hepatic glutathione reductase (GR), glutathione S-transferase (GST), glutamate:cysteine ligase (GCL), and gamma-glutamyl transferase (gammaGT) activities, which ameliorated the glutathione loss and oxidation, and enzyme inactivation, caused by the OP pesticide. Although NAC-treated fish presented a higher survival and were two-fold less likely to die within the study period of 96 h, Cox proportional hazard models showed that hepatic GSH/GSSG ratio was the best explanatory variable related to survival. Hence, tolerance to a lethal concentration of dichlorvos can be explained by the individual capacity to maintain and improve the hepatic glutathione redox status. Impairment of the GSH/GSSG ratio can lead to excessive oxidative stress and inhibition of caspase-3-like activity, inducing cell death by necrosis, and, ultimately, resulting in the death of the organism. We therefore propose a reconsideration of the individual effective dose or individual tolerance concept postulated by Gaddum 50 years ago for the log-normal dose-response relationship. In addition, as NAC increased the tolerance to dichlorvos, it could be a potential antidote for OP poisoning, complementary to current treatments.

Acetylcysteine↗
PubMed2003

Parasitological cure of acute and chronic experimental Chagas disease using the long-acting experimental triazole TAK-187. Activity against drug-resistant Trypanosoma cruzi strains.

We investigated the activity of TAK-187, an experimental antifungal triazole with a long terminal half-life in several experimental animals, against Trypanosoma cruzi. In vitro studies showed that the minimal inhibitory concentration (MIC) against the (extracellular) epimastigote form was 0.3-1 microM, while the corresponding concentration against clinically relevant intracellular amastigotes was 1 nM. At the MIC the endogenous epimastigote C4,14-desmethyl sterols were replaced by di- and tri-methylated sterols, supporting the notion that the primary target of TAK-187 is the parasite's sterol C14alpha demethylase. We investigated the in vivo activity of the compound in a murine model of acute Chagas disease, using T. cruzi strains with different susceptibilities to the drugs currently used clinically (nitrofurans and nitroimidazoles). It was found that TAK-187 given orally at 20 mg/kg induced complete protection against death and high levels (60-100%) of parasitological cures, independently of the infecting strain and even when administered every other day (e.o.d.), consistent with its long terminal half-life in mice. Other experiments, using longer treatment periods were carried out in both acute and chronic models of the disease and showed that TAK-187 given at 10-20 mg/kg e.o.d. induced 80-100% survival with 80-100% of parasitological cures of survivors in both models. No toxic side effects were observed in any of the experimental protocols. TAK-187 is a potent anti-T. cruzi compound with trypanocidal activity in vivo and should be considered for further studies as a potential specific treatment of human Chagas disease.

Acute Disease↗
PubMed2000

Acute lead intoxication in vivo affects myelin membrane morphology and CNPase activity.

The aim of the present study was to assess the sensitivity of central nervous system myelin to acute Pb-toxicity in an animal model, that imitates lead toxicity in occupationally exposed workers, or in occasional incidents of poisoning. Our results indicated that in vivo acute lead intoxication affected both the morphology of myelin and enzymatic activity of the myelin marker, CNPase (2'3'-cyclic nucleotide 3'-phosphodiesterase). The multilayered structure of myelin sheaths was regionally disturbed, with loosely arranged membranes or ovoid-shaped swollen fragments. The activity of CNPase was diminished and Michaelis-Menten kinetics showed a decreased affinity and lower velocity of the enzyme. These data suggest that the disturbances in CNPase activity may contribute, in some extent, to the changes in myelin morphology observed in acute Pb-intoxication.

2',3'-Cyclic-Nucleotide Phosphodiesterases↗