bluuebunny/crossref_metadata_2025_split huggingface dataset:
Determination of the rat tissue partitioning of endotoxin in vitro for physiologically‐based pharmacokinetic (PBPK) modeling
Authors: Ross Ivan A. , Sapienza Philip P. , Hanes Darcy E. , Johnson Widmark , Kim Chung S. 
Published: June 2004

AbstractThe biosynthetically double‐labeled lipopolysaccharide (LPS), containing 3H‐labeled on the fatty acyl‐chains and 14C‐labeled on the glucosamine of Salmonella enterica serotype typhimurium, was isolated from bacteria grown in proteose peptone‐beef extract (PPBE) medium in the presence of labeled precursors; 133 µCi/ml of [2‐3H] acetate sodium salt and 0.167 µCi/ml of N‐acetyl[D‐1‐14C]glucosamine. The LPS was extracted from the bacteria with 90% phenol/chloroform/petroleum ether, puriﬁed and stored in 0.1% (v/v) triethylamine/10 mM Tris HCl at −70 °C. Tissue slices and portions of the meninges were prepared and incubated in artiﬁcial cerebrospinal ﬂuid (CSF) or Krebs phosphate buffer (Krebs) containing 150 ng/ml LPS with [3H] LPS (0.004 µCi/ml, sp. act. 28 µCi/mg LPS). The tissues were incubated under 95% oxygen/5% carbon dioxide at 37 °C with constant agitation until steady‐state uptake was reached (60 min). At the end of the incubation period, tissues were processed for radioactivity measurement. The rat tissue partitioning of LPS in artiﬁcial CSF for brain and Krebs for other organs was measured by using the ratio of tissue to medium at the steady state in vitro. The following results were obtained from the study: Heart, 0.15; liver, 0.19; spleen, 0.12; kidney, 0.18; stomach, 0.17; small intestine, 0.18; brain stem, 0.10; cerebellum, 0.11; meninges, 0.77; hippocampus, 0.12; hypothalamus, 0.12; frontal cortex, 0.09 and caudate nucleus, 0.10. This information, along with plasma or blood/buffer partition coefﬁcients, is a requisite for constructing a physiologically‐based pharmacokinetic (PBPK) model of endotoxins for quantitative risk assessment. Copyright © 2004 John Wiley & Sons, Ltd.
Inhibition of topoisomerase II in 32D.3(G) cells by hydroquinone is associated with cell death
Authors: Fung Jacqueline , Hoffmann Matthew J. , Kim David D. , Snyder Robert 
Published: June 2004

AbstractStudies showing the inhibition of isolated human topoisomerase II (topo II) by benzene metabolites such as hydroquinone, coupled with the recognition that benzene‐induced acute myelogenous leukemia bears a resemblance to second cancers caused by topo II inhibitors such as etoposide, suggested that topo II inhibition by hydroquinone might induce leukemogenic mutations. In these studies the inhibition of topo II by hydroquinone or etoposide was studied in parallel with the effects of these agents on differentiation, maturation and viability in murine bone marrow 32D.3(G) cells. Topoisomerase II of 32D.3(G) cells was inhibited by hydroquinone at concentrations of 5 µM or higher and by etoposide at concentrations of 50 µM or higher. At concentrations of either agent below those that inhibited topo II the cells responded normally to interleukin‐3, which promoted proliferation, and to granulocyte colony‐stimulating factor, which promoted differentiation and maturation. In dose ranges in which topo II was inhibited by either hydroquinone or etoposide, the cells became progressively less viable and cell counts decreased during the incubation period. Progressive inability to detect topo II protein by Western blot analysis as hydroquinone concentrations were increased suggested that either association of the probe with the enzyme was inhibited by hydroquinone or there was degradation of the protein as a function of hydroquinone‐induced apoptosis. Copyright © 2004 John Wiley & Sons, Ltd.
Reactions of nifurtimox with critical sulfhydryl‐containing biomolecules: their potential toxicological relevance
Authors: Díaz E. G. , Montalto de Mecca M. , Castro J. A. 
Published: June 2004

AbstractNifurtimox (Nfx) is a drug used in the treatment of Chagas' disease, an endemic parasitic disease from Latin American countries. It produces undesirable side‐effects in patients, frequently forcing the treatment to be stopped. Its toxic mechanism is not fully understood. In this work we describe purely chemical reactions of Nfx with relevant cellular sulfhydryl (SH) compounds. The compounds tested were glutathione (GSH), cysteine (RSH), lipoic acid (LA) and coenzyme A (CoA). All reacted with Nfx to give nitrite (NO−2). The relative reaction rates were CoA>LA>GSH>RSH. In studies with GSH and RSH the formation of nitrite was accompanied by decreases in Nfx concentration and increases in the formation of a reaction product revealed by HPLC. We failed to show the presence of liver cytosolic GST (GSH transferase activity)‐mediated formation of NO2‐ from Nfx. These NO−2‐releasing processes occurred under in vivo conditions in Nfx‐treated Sprague‐Dawley male rats (240–260 g body weight) at a dose of 100 mg Nfx kg−1 p.o. In urine samples NO−2 excretion was accompanied by unchanged drug and two unidentiﬁed more polar metabolites detectable by HPLC. The Nfx reactions with critical SH from molecules such as GSH, RSH, LA and CoA, and potentially others containing SH residues (e.g. enzymes or structural proteins), might have toxicological relevance not only for the Nfx side‐effects but also for the chemotherapeutic effects on Trypanosoma cruzi. In addition, Nfx reactions with GSH might be crucial in Nfx detoxiﬁcation. Copyright © 2004 John Wiley & Sons, Ltd.
Ultrastructural changes induced in HeLa cells after phototoxic treatment with harmine
Authors: Pérez Martín J. M. , Labrador V. , Fernández Freire P. , Molero M. L. , Hazen M. J. 
Published: June 2004

AbstractIn the present work, we have continued our studies on harmine phototoxicity in human tumour cells. The toxicity of harmine in the dark was analysed by a quantitative neutral red uptake assay, and subcellular sensitive targets following harmine photosensitization were deﬁned by electron microscopic analysis of HeLa cells. The results obtained indicated that this compound shows a clear dose‐dependent cytotoxic effect in the dark. The combined treatment with suitable doses of harmine and UV radiation was very effective at an early stage, although maximal cell killing appeared 48 h after photodynamic activation. Ultrastructural examination of HeLa cells immediately after the photodynamic treatment revealed lysosomal destabilization and profound cytoplasmic vacuolization that evolved to cytolysis, which is typical of necrotic cell death. It is concluded that harmine could be a valuable photosensitizer whose biological applications merit further evaluation. Copyright © 2004 John Wiley & Sons, Ltd.
Bioactivation, toxicokinetics and acute effects of chloroform in fisher 344 and Osborne Mendel Male rats
Authors: Gemma Simonetta , Testai Emanuela , Chieco Pasquale , Vittozzi Luciano 
Published: June 2004

AbstractChloroform has been regarded as a renal carcinogen, based on results obtained with Osborne Mendel (OM) rats. Fisher 344 (F344) rats, considered representative of OM rats on the basis of comparable acute toxic effects, have been used in most of the studies aimed to elucidate the mechanisms of kidney tumour induction. In the present work, in vitro and in vivo chloroform bioactivation in the liver and kidney of F344 and OM rats has been reported, as well as additional toxicokinetics and acute toxicity information. Complete similarity of chloroform metabolism and toxicokinetics was evidenced in the two rat strains. Chloroform metabolism was fully saturated at the OM rat bioassay doses (90–180 mg kg−1 body wt.), working at a maximal rate of 40–50 µmol 14CO2 expired kg−1 h−1. No acute hepatotoxicity, nephrotoxicity or consequent cell proliferation was evidenced at 180 mg kg−1 body wt. chloroform. In the rat liver, phosgene was conﬁrmed as the major metabolite. Renal microsomes from both F344 and OM rats in vitro were unable to produce any oxidative metabolite; at variance, adducts due to oxidative and reductive metabolites were detected in vivo. Our results indicated the presence in the rat kidney of electrophilic metabolites other than phosgene, representing either oxidative metabolites formed elsewhere and sufﬁciently stable to be transported to the kidney or electrophilic metabolites secondary to the formation of reductive radicals. Therefore, the rat kidney represents a suitable model to study the toxicological effects, including genotoxicity, of chloroform metabolites in the absence of cytotoxic effects produced by phosgene formed in situ. Copyright © 2004 John Wiley & Sons, Ltd.
Effects of ochratoxin a on oxidative damage in rat kidney: protective role of melatonin
Authors: Özçelik Nurten , Soyöz Mustafa , Kılınç İbrahim 
Published: June 2004

AbstractEpidemiological studies indicate that ochratoxin A (OTA) may be involved in the pathogenesis of different forms of human nephropathies. Melatonin (MEL) displays antioxidant and free radical scavenger properties. In the present study, the effect of MEL on the oxidative stress induced by OTA administration in rats was investigated. Three groups of eight rats each were used: control, OTA (289 µg kg−1 day−1) and OTA + MEL (OTA, 289 µg kg−1 day−1; MEL, 10 mg kg−1 day−1), with treatment at two different time periods during the same day. After 4 weeks of treatment, the levels of lipid peroxidation (LPO) and the activities of catalase, superoxide dismutase (SOD) and glutathione peroxidase (GSHPx) were measured in homogenates of kidney. In OTA‐treated rats, the levels of LPO and the activities of GSHPx and SOD were signiﬁcantly decreased compared with controls. In OTA + MEL‐treated rats, SOD, GSHPx and catalase activities and LPO levels were not changed signiﬁcantly in comparison with controls. Copyright © 2004 John Wiley & Sons, Ltd.
QT prolongation in anaesthetized guinea‐pigs: an experimental approach for preliminary screening of torsadogenicity of drugs and drug candidates
Authors: Testai L. , Calderone V. , Salvadori A. , Breschi M. C. , Nieri P. , Martinotti E. 
Published: June 2004

AbstractMany non‐cardiovascular drugs can prolong the QT interval of the electrocardiogram (ECG); this is an accessory property not necessary for their pharmacological action and generally linked to the block of the potassium HERG channels and delayed cardiac repolarization. The QT prolongation can lead to a dangerous tachyarrhythmia, called torsade de pointes, and potentially to fatal ventricular ﬁbrillation. The experimental approaches, aimed at an early identiﬁcation of this undesidered property, often require sophisticated and expensive equipment or the use of superior animal species (dog, primates) that cannot be employed easily for ethical and/or economic reasons.This work aimed to study drug‐induced QT prolongation in anaesthetized guinea‐pigs and to evaluate the reliability of such an experimental approach to obtain a satisfying predictive parameter of the torsadogenicity of drugs in humans. Seven drugs that were torsadogenic in humans (astemizole, cisapride, haloperidol, quinidine, sotalol, terfenadine and thioridazine) and two that were non‐torsadogenic (chlorprotixene and diazepam) were administered i.v. to guinea‐pigs under pentobarbital anaesthesia. The ECGs were recorded by four electrodes inserted in the subcutaneous layer of the limbs. Both RR and QT intervals were measured in Leads II and III and then the correct QT values were calculated by Bazett and Fridericia algorithms (QTcB and QTcF, respectively). All the drugs, with the exception of chlorprotixene and diazepam, produced a dose‐dependent prolongation of the QT and RR intervals and a signiﬁcant increase of QTcB and QTcF values. It can be concluded that this method represents a rapid and low‐cost procedure to evaluate the cardiac safety proﬁle in the preliminary screening of a high number of drugs or drug candidates. Copyright © 2004 John Wiley & Sons, Ltd.
Evaluation of lipid peroxidation in red blood cells by monitoring the uptake of sucrose and phenol red
Authors: Sawas A. H. , Pentyala S. N. 
Published: June 2004

AbstractRed blood cells (RBCs) are prone to lipid peroxidation by virtue of their function as oxygen carriers, and also because of their lipid composition. Malondialdehyde (MDA) content using thiobarbituric reagent is widely used to quantify lipid peroxidation. In this study we compare MDA assay with a newly developed assay that evaluates the uptake of sucrose and phenol red into RBCs under peroxidative stress. Both sucrose and phenol red uptake show signiﬁcantly higher correlation with incubation time compared with MDA assay. Furthermore, phenol red uptake into RBCs on treatment with H2O2 has a direct linear proportional relationship, whereas it is hyperbolic with MDA. The assay also clearly shows that uptake of sucrose or phenol red is speciﬁc for intact cells (RBCs) prior to hemolysis. Assay validation is carried out by using known lipid peroxidation‐causing agents, such as ferrous ions, and also by using peroxidation inhibitors such as α‐tocopherol. This new method can be applied efﬁciently to evaluate lipid peroxidation in RBCs as well as other cells and tissues. Copyright © 2004 John Wiley & Sons, Ltd.
Pulmonary irritant potency of polyisocyanate aerosols in rats: comparative assessment of irritant threshold concentrations by bronchoalveolar lavage
Authors: Pauluhn Jürgen 
Published: June 2004

AbstractThe object of this study was to compare the relative acute pulmonary irritant potency of respirable aerosols of a variety of non‐volatile polyisocyanates. The types of polyisocyanates examined included aliphatic homopolymers and mixed aliphatic–aromatic polyisocyanates consisting of the following monomers: HDI (hexamethylene 1,6‐diisocyanate), IPDI (isophorone diisocyanate), MDI (methylene‐diphenyl‐4,4′‐diisocyanate) and TDI (toluene diisocyanate). For reference purposes, the pulmonary irritant polyisocyanate aerosols were compared with monomeric IPDI, a semi‐volatile respiratory tract (airway) irritant. In the substances tested, the concentration of free isocyanate moieties ranged from 11% to 38%. The relative potency to elicit pulmonary irritation was assessed by measurements of lung weights and total protein and lactate dehydrogenase (LDH) in the bronchoalveolar lavage ﬂuid (BALF) following a single 6‐h exposure of male rats. The time course of changes was analysed 3 h and 1, 3 and 7 days after exposure. When exposed to irritant concentrations of aerosol, BALF protein was maximal on post‐exposure day 1 and returned to the level of the controls on post‐exposure day 7. In contrast, rats exposed to sub‐lethal concentrations of monomeric IPDI experienced a time‐related increase in BALF protein. Based on this most sensitive endpoint, extrapolated no‐observed‐effect concentrations (NOECs) were in the range of 2–3 mg m−3 for most polyisocyanates examined. The NOECs from all the substances investigated were in the range 1–50 mg m−3. Thus, this methodology is adequate to rank the pulmonary irritant potency of polyisocyanate aerosols and to differentiate pulmonary from airway irritants. For pulmonary irritants the estimated acute NOECs were essentially similar to the no‐observed‐adverse effect concentrations (NOAECs) from long‐term, repeated‐exposure inhalation studies available for some of the polyisocyanates. A clear dependence of the NOAECs on the content of free isocyanate moieties was not observed. In summary, it is concluded that pulmonary irritation caused by polyisocyanate aerosols can be quantiﬁed readily in an acute rat bioassay by analysis of total protein in BALF. Moreover, this experimental evidence suggests that the NOECs of pulmonary irritants based on this endpoint are predictive of the NOAECs observed after subacute/subchronic inhalation exposure, suggesting that acute pulmonary irritation governs the outcome of repeated inhalation studies with such aerosols. However, for isocyanates where airway irritation predominates the pulmonary irritation, long(er)‐term inhalation studies appear to be indispensable. The content of free NCO per se appears to be a poor predictor of the pulmonary irritant potency of polyisocyanate aerosols. Copyright © 2004 John Wiley & Sons, Ltd.
Endocrine disrupters and human health: could oestrogenic chemicals in body care cosmetics adversely affect breast cancer incidence in women?
Authors: Harvey Philip W. , Darbre Philippa 
Published: June 2004

AbstractIn the decade that has elapsed since the suggestion that exposure of the foetal/developing male to environmental oestrogens could be the cause of subsequent reproductive and developmental effects in men, there has been little deﬁnitive research to provide conclusions to the hypothesis. Issues of exposure and low potency of environmental oestrogens may have reduced concerns. However, the hypothesis that chemicals applied in body care cosmetics (including moisturizers, creams, sprays or lotions applied to axilla or chest or breast areas) may be affecting breast cancer incidence in women presents a different case scenario, not least in the consideration of the exposure issues. The speciﬁc cosmetic type is not relevant but the chemical ingredients in the formulations and the application to the skin is important. The most common group of body care cosmetic formulation excipients, namely p‐hydroxybenzoic acid esters or parabens, have been shown recently to be oestrogenic in vitro and in vivo and now have been detected in human breast tumour tissue, indicating absorption (route and causal associations have yet to be conﬁrmed). The hypothesis for a link between oestrogenic ingredients in underarm and body care cosmetics and breast cancer is forwarded and reviewed here in terms of: data on exposure to body care cosmetics and parabens, including dermal absorption; paraben oestrogenicity; the role of oestrogen in breast cancer; detection of parabens in breast tumours; recent epidemiology studies of underarm cosmetics use and breast cancer; the toxicology database; the current regulatory status of parabens and regulatory toxicology data uncertainties. Notwithstanding the major public health issue of the causes of the rising incidence of breast cancer in women, this call for further research may provide the ﬁrst evidence that environmental factors may be adversely affecting human health by endocrine disruption, because exposure to oestrogenic chemicals through application of body care products (unlike diffuse environmental chemical exposures) should be amenable to evaluation, quantiﬁcation and control. The exposure issues are clear and the exposed population is large, and these factors should provide the necessary impetus to investigate this potential issue of public health. Copyright © 2004 John Wiley & Sons, Ltd.
Inﬂuence of iron (56Fe2O3 or 54Fe2O3) in the upregulation of cytochrome P4501A1 by benzo[a]pyrene in the respiratory tract of Sprague‐Dawley rats
Authors: Garçon Guillaume , Gosset Pierre , Maunit Benoît , Zerimech Farid , Creusy Colette , Muller Jean‐François , Shirali Pirouz 
Published: June 2004

AbstractAny inﬂuence of iron in polycyclic aromatic hydrocarbon (PAH)/iron oxide mixtures on the capacity of PAHs to induce metabolizing enzymes will be one of the ways that iron oxides can affect PAH carcinogenicity. Because cytochromes P450 (CYPs) are haemoproteins, it will be of interest to investigate the possible involvement of Fe2O3 in benzo[a]pyrene (BaP)/Fe2O3 mixtures on the induction of CYP1A1 enzymes in the lung. Male Sprague‐Dawley rats were instilled intratracheally with haematite (56Fe2O3 or 54Fe2O3, 3 mg), BaP (3 mg) or BaP (3 mg) coated onto haematite (56Fe2O3 or 54Fe2O3) particles (3 mg). Firstly, mRNA expressions of cyp1a1 were studied. Secondly, protein concentrations and catalytic activities (7‐ethoxyresoruﬁn O‐deethylase: EROD) of CYP1A1 were determined. Thirdly, 54Fe from BaP/54Fe2O3 mixtures in microsomal proteins was studied using time‐of‐ﬂight laser microprobe mass spectrometry (ToF‐LMMS). Statistically signiﬁcant increases in mRNA expressions, protein concentrations and catalytic activities of CYP1A1 were observed in animals exposed to BaP, to BaP coated onto 56Fe2O3 particles or to BaP coated onto 54Fe2O3 particles versus controls. Both of the BaP/Fe2O3 mixtures induced higher CYP1A1 protein levels and EROD activities than BaP alone. Iron oxide particles per se did not affect mRNA levels of cyp1a1 but only enhanced BaP‐mediated increases of CYP1A1 protein levels and activity. The ToF‐LMMS spectrum proﬁles showed that the 54Fe/56Fe ratio in the microsomes of BaP coated onto 54Fe2O3 particle‐instilled animals was 1.3 instead of the theoretical ratio (i.e. 0.063) observed in BaP coated onto 56Fe2O3 particle‐instilled animals. Taken together, these novel data support the hypothesis that the Fe2O3‐induced increases of the metabolic activation of BaP might rely on the property of Fe2O3 particles to enhance the BaP‐induced translation rate of the cyp1a1 gene into functional haemoproteins. Copyright © 2004 John Wiley & Sons, Ltd.
Casual cell surface remodeling using biocompatible lipid‐poly(ethylene glycol)(n): Development of stealth cells and monitoring of cell membrane behavior in serum‐supplemented conditions
Authors: Chung Hyeyoung A. , Kato Koich , Itoh Chika , Ohhashi Syunsuke , Nagamune Teruyuki 
Published: June 2004

AbstractControl of the cell surface allows modulation of the cell's biological response, producing practical applications and satisfying scientific interests. Consequently, to meet such goals and interests, diverse approaches were developed in cell surface engineering techniques. Poly(ethylene glycol) (PEG) intermediates were widely employed to modify proteins, enzymes, artificial surfaces, liposomes, and drugs for practical usage. PEGylation was also used for modification of cell surface properties. A method was recently developed for the rapid incorporation of proteins into mammalian cell membranes using lipid‐PEG(n) derivatives under physiological conditions. This is a rapid and homogeneous method to incorporate lipid‐PEG(n), which was used as a model to study the modification of cellular properties and cell–cell interactions. Because the stability of molecules incorporated into the cell surface shows the usefulness of the anchoring technique, it was also investigated whether potential factors such as time, the concentration of the incorporated lipid‐PEG(n), and the type of medium affect this incorporation. At concentrations greater than 10 μM, when dual typed lipid‐PEG(n) was incorporated into erythrocytes, antigenic recognition was dramatically attenuated, resulting in the successful development of stealth cells. © 2004 Wiley Periodicals, Inc. J Biomed Mater Res 70A: 179–185, 2004