Showing papers on "Toxicity published in 1994"
TL;DR: The cytotoxic action of A beta on neurons results from free radical damage to susceptible cells, suggesting that A beta activates a member of this class of enzymes.
2,060 citations
TL;DR: Although a consensus was not achieved, operationally it was agreed that 2000 cells per animal and four animals per group was a minimum requirement, in general, the available database suggests that the use of one gender is adequate for screening.
Abstract: The following summary represents a consensus of the working group except where noted. The items discussed are listed in the order in which they appear in the OECD guideline (474) for easy reference. Introduction, purpose, scope, relevance, application and limits of test. The analysis of immature erythrocytes in either bone marrow or peripheral blood is equally acceptable for those species in which the spleen does not remove micronucleated erythrocytes. In the mouse, mature erythrocytes are also an acceptable cell population for micronucleus analysis when the exposure duration exceeds 4 weeks. Test substances. Organic solvents such as DMSO are not recommended. Freshly prepared solutions or suspensions should be used unless stability data demonstrate the acceptability of storage. Vegetable oils are acceptable as solvents or vehicles. Suspension of the test chemicals is acceptable for p.o. or i.p. administration but not for i.v. injection. The use of any unusual solvent should be justified. Selection of species. Any commonly used laboratory rodent species is acceptable. There is no strain preference. Number and sex. The size of experiment (i.e., number of cells per animal, number of animals per group) should be finalized based on statistical considerations. Although a consensus was not achieved, operationally it was agreed that 2000 cells per animal and four animals per group was a minimum requirement. In general, the available database suggests that the use of one gender is adequate for screening. However, if there is evidence indicating a significant difference in the toxicity between male and female, then both sexes should be used. Treatment schedule. No unique treatment schedule can be recommended. Results from extended dose regimens are acceptable as long as positive. For negative studies, toxicity should be demonstrated or the limit dose should be used, and dosing continued until sampling. Dose levels. At least three dose levels separated by a factor between 2 and square root of 10 should be used. The highest dose tested should be the maximum tolerated dose based on mortality, bone marrow cell toxicity, or clinical symptoms of toxicity. The limit dose is 2 g/kg/day for treatment periods of 14 days or less and 1 g/kg/day for treatment periods greater than 14 days. A single dose level (the limit dose) is acceptable if there is no evidence of toxicity. Controls. Concurrent solvent (vehicle) controls should be included at all sampling times. A pretreatment sample, however, may also be acceptable only in the short treatment period peripheral blood studies. A concurrent positive control group should be included for each experiment.(ABSTRACT TRUNCATED AT 400 WORDS)
373 citations
TL;DR: Protein tyrosine kinase inhibitors of the tyrphostin AG 126 family protect mice against LPS-induced lethal toxicity, and correlates with the ability of these agents to block L PS-induced production of tumor necrosis factor alpha and nitric oxide in macrophages as well as TNF-alpha in vivo.
Abstract: Septic shock results from excessive stimulation of the host immune system, especially macrophages, by lipopolysaccharide (LPS), or endotoxin, which resides on the outer membrane of bacteria. Protein tyrosine kinase inhibitors of the tyrphostin AG 126 family protect mice against LPS-induced lethal toxicity. The protection correlates with the ability of these agents to block LPS-induced production of tumor necrosis factor alpha (TNF-alpha) and nitric oxide in macrophages as well as LPS-induced production of TNF-alpha in vivo. Furthermore, this inhibitory effect correlated with the potency of AG 126 to block LPS-induced tyrosine phosphorylation of a p42MAPK protein substrate in the murine macrophage.
345 citations
TL;DR: In vivo evidence is provided that AFB1 can cause lipid peroxidation in rat liver and that pretreatment with selenium and vitamin E, both antioxidants, and deferoxamine, a specific iron chelator, significantly inhibited lipid per Oxidative damages as well as liver cell damage.
219 citations
TL;DR: The lethal concentration and the threshold for toxicity of the olefin are less than previously reported, and thereshold for nephrotoxicity reaches the range of values for the oalfin that have been attained in clinical practice.
Abstract: BackgroundSoda lime converts sevoflurane to CF2 == C(CF3)OCH2F, an olefin called compound A, whose toxicity raises concerns regarding the safe administration of sevoflurane via rebreathing circuits. The present report extends the findings of a previous investigation by others of the toxicity of this
199 citations
TL;DR: Modulation of GSH levels effect the toxicity of alkylating agents and that GSH influences the mode of cell death induced by alkyLating agents are suggested.
199 citations
TL;DR: There has been a continuous search for biological and pharmacological strategies to protect the renal function and thus permit the administration of high quantities of the drug; these strategies include modification of administration modes, development of new galenic forms, and the use of chemoprotectors, among others.
Abstract: Cisplatin, or cis-diamminedichloroplatinum(II) (CDDP), is an antineoplastic agent developed in 1965 by Rosenberg et al. [70], who were studying the effects of electrolysis products from a platinum electrode on growing cells. Cisplatin was clinically tested in 1972 by Hill et al. [40]. In spite of its good antineoplastic activity against ovarian, lung, bladder, breast, head and neck.~ and testicular cancer, its clinical use was rapidly limited due to unexpected and very severe renal toxicity. Acute and cumulative renal toxicity associated with histological damage has been shown in both animal and human studies. Several theories concerning the pathophysiological mechanism behind this toxicity have been suggested [13, 59]. Since the therapeutic efficacy of cisplatin seems to be proportional to the delivered dose [80], there has been a continuous search for biological and pharmacological strategies to protect the renal function and thus permit the administration of high quantities of the drug; these strategies include modification of administration modes, development of new galenic forms, and the use of chemoprotectors, among others. Additionally, other platinum analogs with less nephrotoxicity have been studied, but these agents have less antitumor activity than cisplatin or have other inherent toxicities restricting their use [78].
199 citations
TL;DR: Several clinical variables that influence MTX disposition that, when modified, can reduce the frequency of high-risk MTX concentrations and toxicity are identified.
Abstract: PURPOSEFollowing high-dose methotrexate (HD-MTX) treatment, delayed MTX elimination is an important problem because it necessitates increased leucovorin rescue and additional hospitalization for hydration and urinary alkalinization. Our purpose was to identify factors associated with high-risk MTX plasma concentrations (defined by plasma concentration > or = 1.0 mumol/L at 42 hours from the start of MTX) and with toxicity.PATIENTS AND METHODSVariables associated with MTX concentrations and toxicity were assessed in 134 children treated with one to five courses of HD-MTX (900 to 3,700 mg/m2 intravenously [i.v.] over 24 hours for a total of 481 courses) for acute lymphoblastic leukemia (ALL).RESULTSHigh-risk MTX concentrations, toxicity (usually mild mucositis), and delay in resuming continuation chemotherapy occurred in 106 (22%), 123 (26%), and 66 (14%) of 481 courses, respectively. Using a mixed effects model for repeated measures, high-risk MTX concentrations were significantly associated with a higher ...
198 citations
TL;DR: Quantification of these unesterified oxysterols in LDL extracts and comparison with the toxicity of authentic standards indicate that 7-ketocholesterol and 7-hydroxycholesterol are present in Ox-LDL at levels sufficient to account for its toxicity to SMCs.
Abstract: The cytotoxicity of oxidized low-density lipoprotein (Ox-LDL) to arterial smooth muscle cells (SMCs) may contribute to atherogenesis by causing cell death in core regions of plaques. The aim of the present study was to identify the components of copper-oxidized LDL responsible for its toxicity to porcine aortic SMCs. Toxicity to SMCs was assessed as the decrease in viable cell counts after 3-day cell incubation. Extracts of LDL were tested for toxicity at concentrations equivalent to that derived from 100 micrograms LDL protein per milliliter. Lipid extracts of Ox-LDL but not native-LDL were toxic to SMCs. When separated into neutral and polar lipid classes, only the neutral lipids were toxic (89.7 +/- 0.7% cell loss). The neutral lipids were fractionated further by use of solid-phase extraction and high-performance liquid chromatography (HPLC). Two toxic fractions, causing 93.3% and 60.3% cell loss, were isolated from HPLC and analyzed by gas chromatography/mass spectrometry. The most toxic of these fractions contained 7-ketocholesterol, and the other contained 7 alpha- and 7 beta-hydroxycholesterol. Quantification of these unesterified oxysterols in LDL extracts and comparison with the toxicity of authentic standards indicate that 7-ketocholesterol and 7-hydroxycholesterol are present in Ox-LDL at levels sufficient to account for its toxicity to SMCs.
187 citations
TL;DR: Cylindrospermopsin caused significant cell death and GSH is involved in the detoxification of CY in cultured hepatocytes, and lower, nontoxic doses of CY decreased cell glutathione (GSH) to about 50% of control.
162 citations
TL;DR: Improving morbidity related to drug hepatotoxicity relies on a free flow of information between manufacturers and practitioners in order to optimize detection of potentially serious liver damage, and advances in pharmacogenetics toward a better identification of those at particular risk for developing drug-related liver toxicity.
Abstract: Although the liver is particularly exposed to drugs and their metabolites, hepatic side-effects of antibiotics are far less frequent than other adverse effects such as gastrointestinal disorders or cutaneous reactions. However, the potential severity of hepatic side-effects for some drugs is stressed. Antibiotic related liver injuries cover most of the clinical and pathological expressions of hepatic dysfunction, including cytotoxic hepatitis (isoniazid), intrahepatic cholestasis (macrolides, penicillins, clavulanic acid), mixed hepatitis (sulphonamides), chronic active hepatitis (nitrofurantoin), or microvesicular steatosis (tetracycline). In most cases, toxicity is idiosyncratic, reactions occurring only in some susceptible individuals. The mechanisms underlying toxicity may be primarily metabolite-dependent (isoniazid), hypersensitivity-mediated (beta-lactams), or result from both processes (sulphonamides, erythromycin derivatives). In some cases, the liver is not the primary target organ for toxicity but appears to mediate the clinical expression of some adverse effects induced by antibiotics. The most significant example of this is hypoprothrombinaemia due to the inhibition of hepatic gamma-carboxylation of vitamin K-dependent clotting factors by sulphydryl group-containing cephalosporins. Inhibition of bilirubin conjugation or transport by rifampicin or fusidic acid may also be viewed as hepatic side-effects of antibiotics. Ascertaining the casual relationship of a given drug to an hepatic adverse effect may prove particularly difficult, because of the potential contribution of host status and concurrent medications. Diagnosis is based mainly on circumstantial evidence, i.e. the temporal relationship between drug administration (or withdrawal) and the time-course of liver dysfunction. Improving morbidity related to drug hepatotoxicity relies on a free flow of information between manufacturers and practitioners in order to optimize detection of potentially serious liver damage, and advances in pharmacogenetics toward a better identification of those at particular risk for developing drug-related liver toxicity.
01 Feb 1994-Comparative Biochemistry and Physiology Part C: Pharmacology, Toxicology and Endocrinology
TL;DR: This review summarises the relatively dispersed toxicity literature on intermittent exposures and suggests that the short-lived nature of intermittent exposures suggests that equilibriums in poison concentrations between the external environment and the body compartments of the test species are not achieved.
TL;DR: The use of this test system as an alternative method to testing toxicity in adult fish is discussed, and the effective concentrations and the lowest effect concentrations investigated in this preliminary study were comparable to the LC50 values for adult fish.
Abstract: Acute toxicity testing in fish is a standard method used in estimating the influences of chemicals on aquatic vertebrates. The ecotoxicological data obtained from acute toxicity tests in fish are, ...
Journal Article•
TL;DR: Swainsonine, an α-mannosidase inhibitor which blocks Golgi oligosaccharide processing, represents a new class of compounds that inhibit both rate of tumor growth, and metastasis, in murine experimental tumor models as mentioned in this paper.
Abstract: Swainsonine, an α-mannosidase inhibitor which blocks Golgi oligosaccharide processing, represents a new class of compounds that inhibit both rate of tumor growth, and metastasis, in murine experimental tumor models. In this first phase I study, the quantitative and qualitative toxicities of swainsonine have been studied in patients given a continuous i.v. infusion over 5 days, repeated at 28-day intervals. Dose levels were escalated in increments of 100 µg/kg/day from 50–550 µg/kg/day. Nineteen patients with both solid tumor and hematological malignancies were given a total of 31 courses. Hepatotoxicity, particularly in patients with liver metastases, was the dose-limiting toxicity. The maximum tolerated dose (MTD) and the recommended starting dose (MTD -1 level) were 550 and 450 µg/kg/day, respectively. Common side effects included edema, mild liver dysfunction, a rise in serum amylase, and decreased serum retinol. Acute respiratory distress syndrome possibly precipitated by swainsonine resulted in a treatment-related death in a patient with significant pretreatment hepatic dysfunction. One patient with head and neck cancer showed >50% shrinkage of tumor mass for 6 weeks after treatment. Two patients with lymphangitis carcinomatosis on chest X-ray noted improvement in cough and shortness of breath during the infusion of swainsonine and for 1 week thereafter. Clearance and serum half-life for swainsonine were determined to be approximately 2 ml/h/kg, and 0.5 day, respectively. Golgi oligosaccharide processing, a putative anticancer target for swainsonine was inhibited in peripheral blood lymphocytes as evidenced by a marked decrease in leukoagglutinin binding after 5 days of treatment. Oligomannosides in patient urine increased 5-to 10-fold over the 5 days of treatment, indicating that tissue lysosomal α-mannosidases were also blocked by swainsonine. Urine oligomannoside accumulation reached steady state at 3 days, approximately 1 day after serum drug levels reached steady state. The fraction of HLA-DR-positive cells in peripheral blood lymphocytes increased following 5 days of swainsonine treatment, an effect similar to that observed for peripheral blood lymphocytes from normal subjects cultured with swainsonine. No significant changes in CD3, CD4, CD8, CD16, and CD25 were observed. Swainsonine produces minimal toxicity when administered i.v. to cancer patients at dosages that inhibit both Golgi α-mannosidase II and lysosomal α-mannosidases. Detection of hepatic metastases or liver enzyme abnormalities prior to treatment predict for more significant toxicity.
Journal Article•
TL;DR: Flutamide is toxic to rat hepatocytes as a result of the cytochrome P450 (3A and also 1A)-mediated formation of electrophilic metabolites, whose damaging effects are further aggravated by the inhibitory effect of flutamide on mitochondrial respiration and ATP formation.
Abstract: The hepatotoxicity of flutamide, an antiandrogen that produces hepatitis in some human recipients, was studied in isolated rat hepatocytes. Flutamide (1 mM) led to the covalent binding of reactive electrophilic metabolites to male rat hepatocyte proteins. It decreased the reduced glutathione (GSH)/glutathione disulfide ratio and total protein thiols. This was associated with an early increase in phosphorylase a activity (a Ca(++)-dependent enzyme) and a decrease in cytoskeleton-associated protein thiols, the formation of plasma membrane blebs, the release of lactate dehydrogenase (LDH) and a loss of cell viability. Both covalent binding and LDH release were decreased by piperonyl butoxide (an inhibitor of cytochrome P450) and increased by dexamethasone pretreatment (which induces cytochrome P450 3A). The toxicity was increased by beta-naphthoflavone (which induces cytochrome P450 1A). Hepatocytes from female rats (which lack cytochrome P450 3A2) exhibited lower covalent binding and lower LDH release. The addition of cystine (a GSH precursor) increased hepatocellular GSH and decreased LDH release in male hepatocytes. The administration of a diet deficient in sulfur-containing amino acids had the opposite effects; it produced toxicity with 100 microM flutamide. Flutamide (50 microM) markedly inhibited respiration (mainly at the level of complex I) in isolated male rat liver mitochondria and flutamide (1 mM) decreased ATP levels in isolated male rat hepatocytes. It was concluded that flutamide is toxic to rat hepatocytes as a result of the cytochrome P450 (3A and also 1A)-mediated formation of electrophilic metabolites, whose damaging effects are further aggravated by the inhibitory effect of flutamide on mitochondrial respiration and ATP formation.
TL;DR: It is concluded that further studies, using more sensitive endpoints than rubidium leakage, are needed before it can be decided whether or not freshly isolated rainbow trout hepatocytes are suitable in routine toxicity testing.
TL;DR: The kidney, liver, and bone marrow (megakaryocytic lineage) were identified as the major target organs for toxicity with rel A antisense therapy with phosphorothioate antisense oligonucleotides.
Abstract: To characterize the in vivo toxicity of phosphorothioate antisense oligonucleotides against rel A (p65 subunit of NF-κB transcription factor), forty-eight 6-week-old CD-1 mice were split into 4 groups (6/sex/group) receiving vehicle (phosphate-buffered saline) or doses of 50, 100, and 150 mg/kg of rel A antisense oligonucleotides intraperitoneally 3 times weekly for 2 weeks. Clinical signs of toxicity included weakness, and decreased motor activity and food consumption with body weight loss. Mortality occurred in 7 of 12 mice in the 150-mg/kg group and in 2 of 12 mice in the 100-mg/kg group, most of which died within the first 2 to 4 days of treatment. The remaining mice were necropsied on day 15. The major hematological finding was severe dose-dependent thrombocytopenia. The liver enzyme levels were mildly elevated in the serum of mid- and high-dose animals. At necropsy, increased spleen and liver weights were observed in treated mice, some of which also had mild pleural and/or peritoneal effusions. Hist...
TL;DR: Cell killing by the various thiols correlated better with the ratio between the half-lives for thiol oxidation and reaction of thiol with H2O2 than with either reaction rate alone, which suggests that the toxicity pattern and magnitude of cell killing in V79 cells by variousThiols depend on the interplay between the rate of thiola oxidation and the rates of reaction between the thiol and the H2 O2 produced in theThiol oxidation.
Abstract: When Chinese hamster V79 cells are exposed to various thiol compounds in phosphate-buffered saline (PBS), some compounds cause toxicity (loss of colony formation), although the dependence on drug concentration and the magnitude of the cell killing vary between the different thiols. For example: dithiothreitol (DTT) and WR-1065 cause a biphasic toxicity whereby cell killing occurs at about 0.2 to 1.0 mM thiol, but is not seen at higher or lower drug concentrations; N-acetylcysteine (NAC) is toxic only at concentrations 22 mM and shows no biphasic pattern; and glutathione (GSH) and penicillamine are only minimally toxic at all concentrations. The effect of the addition of 1 pM Cu2? to the thiol also depends on the particular thiol: e.g., Cu2' increases cell killing in the biphasic pattern with WR-1065; it increases the toxicity of NAC only at high thiol concentrations; and it elicits a 'slight toxicity in the biphasic pattern by GSH and penicillamine. In all cases tested, if the thiol is toxic, the cell killing can be decreased or prevented by addition of catalase, consistent with the hypothesis that the toxicity is mediated through H202 produced during the thiol oxidation. However, when the oxidation rates of the various thiols in PBS without and with Cu2, were measured, the data did not show a simple correlation between the toxicity of the various thiols and their oxidation rates. The rate of the reaction of the various thiols with H202 was also determined and showed a better, but still not good, correlation with toxicity. However, cell killing by the various thiols correlated better with the ratio between the half-lives for thiol oxidation and reaction of thiol with H202 than with either reaction rate alone. This suggests that the toxicity pattern and magnitude of cell killing in V79 cells by various thiols depend on the interplay between the rate of thiol oxidation and the rate of reaction between the thiol and the H202 produced in the thiol oxidation.
TL;DR: The toxicity of terbufos, trichlorfon, 4 nitrophenols, and 2,4-dinitrophenol to rainbow trout (Oncorhynchus mykiss) and the amphipod Gammarus pseudohmnaeus was investigated in this article.
Abstract: Acute toxicity tests were conducted to determine (a) the individual and interactive effects of water temperature (7, 12, 17°C), pH (6 5, 7 5, 8 5, 9 5), and time on the toxicity of terbufos, trichlorfon, 4 nitrophenol, and 2,4-dinitrophenol to rainbow trout (Oncorhynchus mykiss) and the amphipod Gammarus pseudohmnaeus, and (b) the individual and interactive effects of water temperature and pH on chemical bioconcentration during acute tests with rainbow trout and Gammarus exposed to terbufos, 4 nitrophenol, and 2,4 dinitrophenol The toxicity of all four chemicals was significantly affected by pH in all tests, except for Gammarus exposed to terbufos The toxicity of terbufos to rainbow trout and Gammarus was less at pH 7 5 than at higher or lower pH The toxicity of both nitrophenols decreased as pH increased, whereas the toxicity of trichlorfon increased with pH The effect of pH on trichlorfon toxicity decreased with temperature Temperature significantly affected the toxicity of all four chemicals to both species Toxicity increased with temperature in all tests, except for rainbow trout exposed to nitrophenols, toxicity decreased as temperature increased for rainbow trout Chemical bioconcentration was also significantly af fected by temperature and pH and was directly related to toxicity in most tests Significant interactive effects between toxicity modifying factors were also frequently observed Temperature and pH effects on chemical toxicity need to be consid ered in chemical hazard assessment to ensure adequate protection of aquatic organisms
TL;DR: The sensitivity of MetPLATE™ to heavy metals was generally higher than Microtox and was of the same order as or better than Daphnia and fish bioassay.
Abstract: A rapid, quantitative microbial assay, which is specific for heavy metal toxicity, has been developed. The assay (MetPLATE) is in a 96-well microtitration plate format and is suitable for determining toxicity characteristics such as median inhibitory concentrations. The sensitivity of MetPLATE to heavy metals [Cu, Zn, Cd, Pb, Hg, Cr(III)] was generally higher than Microtox and was of the same order as or better than Daphnia and fish bioassay. MetPLATE was insensitive to organic compounds at concentrations higher than those found in the environment. Six out of 10 industrial wastewaters or process waters surveyed were toxic. Heavy metal analysis of these waters confirmed the presence of heavy metals in the toxic samples. MetPLATE can be run concurrently with other assays for general toxicity to help determine the nature of chemicals causing toxicity.
TL;DR: Findings suggest that an antioxidant inhibitor of lipid peroxidation limits CsA-induced renal toxicity in vitro and in vivo and suggest a pathogenic role for ROS-mediated lipidperoxidation in Cs a-induced kidney toxicity in humans.
Abstract: The exact mechanisms by which cyclosporine (CsA) causes renal injury is not known. The possibility that reactive oxygen species (ROS) may play a role, since CsA induces renal microsomal lipid peroxidation and reduces glutathione levels, was investigated by examining whether administration of an antioxidant attenuates CsA-induced nephrotoxicity. One of three groups of uninephrectomized rats received vehicles, another CsA 25 mg/kg/day and the third, CsA plus antioxidant lazaroid (U-74389 G) 20 mg/kg/day, for 8 weeks. CsA-induced functional and structural derangements were accompanied by a significant induction of renal cortical lipid peroxidation (thiobarbituric acid reactive substances and conjugated diene). Administration of lazaroid significantly suppressed CsA-induced lipid peroxidation and provided significant functional and structural protection. That lazaroid affords renal functional protection against CsA in the rat was again demonstrable in a crossover study. To examine the relation between CsA nephrotoxicity and lipid peroxidation, cell culture studies were undertaken. CsA induced renal epithelial (LLC-PK1) cell injury (LDH release) as well as lipid peroxidation and degradation (prelabeled 3H arachidonic acid release). Lazaroid prevented CsA-induced cell injury and limited lipid alterations. These new findings--that an antioxidant inhibitor of lipid peroxidation limits CsA-induced renal toxicity in vitro and in vivo--suggest a pathogenic role for ROS-mediated lipid peroxidation in CsA-induced renal toxicity. Antioxidant therapy may minimize CsA-induced renal toxicity in humans.
TL;DR: Treatment-related histopathological changes were observed in the thymus, thyroid, bone marrow, and liver of rats exposed to the 10 ppb diet, but increased frequency of mild changes was observed in most of these tissues at the 1.0 ppb level.
TL;DR: It appeared that advancing age with chronic renal, cardiac and pulmonary insufficiency contributed to acetaminophen toxicity in this patient.
TL;DR: This study supports the wide safety margin of policosanol when administered chronically and effects on body weight gain, food consumption, clinical observations, blood biochemistry, hematology, organ weight ratios and histopathological findings were similar in control and treated groups.
TL;DR: Data indicate a broader specificity for activity in the adult nervous system than that in the developing system and suggest differing mechanisms for the two effects, consistent with previous reports.
TL;DR: The hypothesis that diverse insults can produce developmental toxicity, in part, by altering maternal and embryonic Zn metabolism is supported.
TL;DR: It is demonstrated that p-cresol is the most toxic cResol isomer in rat liver tissue and that its toxicity is dependent on the formation of a reactive intermediate, and the mechanism(s) of toxicity of the o- and m-isomers may differ from that of p- cresol.
TL;DR: Pregnant New Zealand white rabbits were injected subcutaneously on gestational day 12 with a teratogenic dose of HU in the presence or absence of 550 mg/kg of D-mannitol (Man), a specific scavenger of hydroxyl free radicals, and the teratologic effects of H U were ameliorated by Man as evidenced by decreased incidences of the expected limb malformations.
Abstract: Hydroxyurea (HU) is a potent mammalian teratogen. Within 2–4 hours after maternal injection, HU causes 1) a rapid episode of embryonic cell death and 2) profound inhibition of embryonic DNA synthesis. A variety of antioxidants delays the onset of embryonic cell death and reduces the incidence of birth defects. Antioxidants do not block the inhibition of DNA synthesis, indicating that early embryonic cell death is not caused by inhibited DNA synthesis. We have suggested that some HU molecules may react within the embryo to produce H2O2 and subsequent free radicals, including the very reactive hydroxyl free radical. The free radicals could cause the early cell death; antioxidants are believed to terminate the aberrant free radical reactions resulting in lessened developmental toxicity. To investigate whether hydroxyl free radicals cause the early episode of cell death, pregnant New Zealand white rabbits were injected subcutaneously on gestational day 12 with a teratogenic dose of HU (650 mg/kg) in the presence or absence of 550 mg/kg of D–mannitol (Man), a specific scavenger of hydroxyl free radicals. Osmotic control rabbits received HU plus 550 mg/kg of xylose (Xyl, a nonactive aldose). At term, the teratologic effects of HU were ameliorated by Man as evidenced by decreased incidences of the expected limb malformations. Xyl exerted no demonstrable effect on HU teratogenesis. Histological examination of limb buds at 3–8 hours after maternal injection, showed that Man delayed the onset of HU–induced cell death by as much as 4 hours. Xyl had no effect. That Man acts within the embryo was shown by performing intracoelomic injections on alternate implantation sites with Man, Xyl, or saline followed by subcutaneous injection of the pregnant doe with HU. Embryos were harvested 3–8 hours later. Limb buds from saline– and Xyl–injected embryos exhibited the typical pattern of widespread HU–induced cell death at 3–4 hours, whereas Man–injected embryos did not exhibit cell death until 5–8 hours. These results are consistent with those reported for antioxidant–mediated amelioration of HU–induced developmental toxicity and with the hypothesis that hydroxyl free radicals are the proximate reactive species in HU–induced early embryonic cell death. © 1994 Wiley-Liss, Inc.
TL;DR: In this article, the effects of soluble silicon (Si) on the toxicity of aluminium (Al) to soybean roots were investigated in solution culture, and it was shown that the pH-dependent affinity of Si for Al in dilute solutions, and the consequent formation of sub-colloidal inert hydroxyaluminosilicate species, is the basis for the alleviation of Al toxicity by Si.
Abstract: The effects of soluble silicon (Si) on the toxicity of aluminium (Al) to soybean roots were investigated in solution culture. A weak nutrient solution which included a low concentration of phosphorus (P) was shown to be necessary to allow the full expression of Al toxicity. As solution pH decreased below 6, reductions in root growth in the presence of Al became increasingly severe. Silicon alleviated the symptoms of Al toxicity, but the effective rate was dependent on pH. Greater concentrations of Si were required at lower pH where Al was more toxic. These results support the hypothesis that the pH‐dependent affinity of Si for Al in dilute solutions, and the consequent formation of sub‐colloidal inert hydroxyaluminosilicate species, is the basis for the alleviation of Al toxicity by Si.
Journal Article•
TL;DR: Glutathione status may play an important role in the susceptibility to toxicity and the findings suggest that the SEC is the initial in vivo target of dacarbazine due to a relatively higher level of metabolic activation that more readily overcomes the available detoxification.
Abstract: The pathophysiology of hepatic veno-occlusive disease is poorly understood. These studies were undertaken to determine the initial cellular target and the role of glutathione detoxification of dacarbazine, a toxin implicated in hepatic veno-occlusive disease. Sinusoidal endothelial cells (SECs) and hepatocytes were isolated and plated in culture dishes. Dacarbazine (5-(3,3-dimethyl-triazeno) imidazole-4-carboxamide), 3 and 6 mM, was toxic to SECs but not to hepatocytes. Onset of toxicity occurred between 11 and 12 hr as determined by serial MTT assays and ethidium homodimer dye exclusion. Glutathione detoxification of dacarbazine in SECs was suggested by: (1) depletion of glutathione before onset of toxicity; (2) exacerbation of toxicity by buthionine sulfoximine (BSO) depletion of glutathione; and (3) protection by exogenous glutathione. Protection by exogenous glutathione may be by uptake of intact tripeptide rather than by extracellular hydrolysis: neither acivicin (inhibitor of gamma-glutamyltranspeptidase) nor BSO (inhibitor of gamma-glutamylcysteine synthetase) blocked the protective effect, and glutathione disulfide did not protect. The relative resistance to dacarbazine toxicity seen in hepatocytes is not due to more efficient GSH detoxification, because toxicity was not unmasked in hepatocytes cultures in medium lacking sulfur amino acid precursors of GSH. In conclusion, glutathione status may play an important role in the susceptibility to toxicity. Furthermore, the findings suggest that the SEC is the initial in vivo target of dacarbazine due to a relatively higher level of metabolic activation that more readily overcomes the available detoxification.