Showing papers on "Toxicity published in 2004"

β-Cell Glucose Toxicity, Lipotoxicity, and Chronic Oxidative Stress in Type 2 Diabetes

Abstract: The relentless decline in β-cell function frequently observed in type 2 diabetic patients, despite optimal drug management, has variously been attributed to glucose toxicity and lipotoxicity. The former theory posits hyperglycemia, an outcome of the disease, as a secondary force that further damages β-cells. The latter theory suggests that the often-associated defect of hyperlipidemia is a primary cause of β-cell dysfunction. We review evidence that patients with type 2 diabetes continually undergo oxidative stress, that elevated glucose concentrations increase levels of reactive oxygen species in β-cells, that islets have intrinsically low antioxidant enzyme defenses, that antioxidant drugs and overexpression of antioxidant enzymes protect β-cells from glucose toxicity, and that lipotoxicity, to the extent it can be attributable to hyperlipidemia, occurs only in the context of preexisting hyperglycemia, whereas glucose toxicity can occur in the absence of hyperlipidemia.

Manganese toxicity upon overexposure

Abstract: Manganese (Mn) is a required element and a metabolic byproduct of the contrast agent mangafodipir trisodium (MnDPDP). The Mn released from MnDPDP is initially sequestered by the liver for first-pass elimination, which allows an enhanced contrast for diagnostic imaging. The administration of intravenous Mn impacts its homeostatic balance in the human body and can lead to toxicity. Human Mn deficiency has been reported in patients on parenteral nutrition and in micronutrient studies. Mn toxicity has been reported through occupational (e.g. welder) and dietary overexposure and is evidenced primarily in the central nervous system, although lung, cardiac, liver, reproductive and fetal toxicity have been noted. Mn neurotoxicity results from an accumulation of the metal in brain tissue and results in a progressive disorder of the extrapyramidal system which is similar to Parkinson's disease. In order for Mn to distribute from blood into brain tissue, it must cross either the blood-brain barrier (BBB) or the blood-cerebrospinal fluid barrier (BCB). Brain import, with no evidence of export, would lead to brain Mn accumulation and neurotoxicity. The mechanism for the neurodegenerative damage specific to select brain regions is not clearly understood. Disturbances in iron homeostasis and the valence state of Mn have been implicated as key factors in contributing to Mn toxicity. Chelation therapy with EDTA and supplementation with levodopa are the current treatment options, which are mildly and transiently efficacious. In conclusion, repeated administration of Mn, or compounds that readily release Mn, may increase the risk of Mn-induced toxicity.

Oxidative Stress, Toxicology, and Pharmacology of CYP2E1*

Abstract: This review describes some of the biochemical and toxicological properties of CYP2E1, especially as it relates to alcohol metabolism and toxicity and the establishment of human hepatoma HepG2 cell lines that overexpress human CYP2E1. Ethanol, polyunsaturated fatty acids, and iron were found to be cytotoxic in HepG2 cells that overexpress CYP2E1. GSH appears to be essential in protecting HepG2 cells against the CYP2E1-dependent cytotoxicity, and GSH levels were elevated owing to a twofold increase in activity and expression of glutamate cysteine ligase. We suggest that this up-regulation of GSH synthesis was an adaptive response to attenuate CYP2E1-dependent oxidative stress and toxicity. Induction of a state of oxidative stress appears to play a central role in the CYP2E1-dependent cytotoxicity. Mitochondrial membrane potential decreased in the CYP2E1-expressing HepG2 cells, and this decrease shared similar characteristics with the developing toxicity. Alcohol-dependent liver injury is likely to be a multifactorial process involving several mechanisms. We believe that the linkage between CYP2E1-dependent oxidative stress, mitochondrial injury, and GSH homeostasis contribute to the toxic actions of ethanol on the liver.

A critical analysis of the causes of boron toxicity in plants

Abstract: This study investigated the main factors contributing to boron toxicity in plants. Growth was rapidly inhibited by internal B concentrations in the range 1–5 m m across a range of plant types that included monocot, dicot and algal species. In contrast, mature cells were able to withstand up to 60 m m B for several days. In wheat, rapid inhibition of root growth occurred if high B was applied to the root tip, but not if high B was applied to mature sections of the root. In leaves, there were gradations in B concentrations that correlated with visible symptoms of toxicity. However, there was no evidence to support the hypothesis that toxicity in leaves is due to osmotic stress induced by the accumulation of B. Analysis of the sensitivity to B of a range of metabolic processes including photosynthesis, respiration and protein synthesis leads to the conclusion that growth is not restricted by effects of B on energy supply and not directly by inhibition of protein synthesis. At higher B concentrations, many cellular activities were found to be partially inhibited and the toxicity to mature tissues was therefore considered not to arise from the disruption of a single process, but from the accumulated retardation of many cellular processes, exacerbated in light by photo-oxidative stress.

Immune Cell Regulation and Cardiovascular Effects of Sphingosine 1-Phosphate Receptor Agonists in Rodents Are Mediated via Distinct Receptor Subtypes

Abstract: Sphingosine 1-phosphate (S1P) is a bioactive lysolipid with pleiotropic functions mediated through a family of G protein-coupled receptors, S1P(1,2,3,4,5). Physiological effects of S1P receptor agonists include regulation of cardiovascular function and immunosuppression via redistribution of lymphocytes from blood to secondary lymphoid organs. The phosphorylated metabolite of the immunosuppressant agent FTY720 (2-amino-2-(2-[4-octylphenyl]ethyl)-1,3-propanediol) and other phosphonate analogs with differential receptor selectivity were investigated. No significant species differences in compound potency or rank order of activity on receptors cloned from human, murine, and rat sources were observed. All synthetic analogs were high-affinity agonists on S1P(1), with IC(50) values for ligand binding between 0.3 and 14 nM. The correlation between S1P(1) receptor activation and the ED(50) for lymphocyte reduction was highly significant (p < 0.001) and lower for the other receptors. In contrast to S1P(1)-mediated effects on lymphocyte recirculation, three lines of evidence link S1P(3) receptor activity with acute toxicity and cardiovascular regulation: compound potency on S1P(3) correlated with toxicity and bradycardia; the shift in potency of phosphorylated-FTY720 for inducing lymphopenia versus bradycardia and hypertension was consistent with affinity for S1P(1) relative to S1P(3); and toxicity, bradycardia, and hypertension were absent in S1P(3)(-/-) mice. Blood pressure effects of agonists in anesthetized rats were complex, whereas hypertension was the predominant effect in conscious rats and mice. Immunolocalization of S1P(3) in rodent heart revealed abundant expression on myocytes and perivascular smooth muscle cells consistent with regulation of bradycardia and hypertension, whereas S1P(1) expression was restricted to the vascular endothelium.

Safety, Pharmacokinetics, and Activity of ABX-EGF, a Fully Human Anti–Epidermal Growth Factor Receptor Monoclonal Antibody in Patients With Metastatic Renal Cell Cancer

Abstract: Purpose To determine the antitumor activity of ABX-EGF, a fully human monoclonal antibody to the epidermal growth factor receptor (EGFr), in previously treated patients with metastatic renal cell carcinoma, and to characterize its toxicity, immunogenicity, pharmacokinetics, and pharmacodynamics. Patients and Methods The antitumor activity, as well as the toxicity, pharmacokinetics, pharmacodynamics, and immunogenicity of ABX-EGF, were assessed. Results Eighty-eight patients were treated with ABX-EGF doses of 1.0, 1.5, 2.0, or 2.5 mg/kg weekly with no loading dose. EGFr immunostaining was performed on 76 tumor biopsy specimens (86%), and 69 (91%) scored positive. Major responses occurred in three patients, and two patients had minor responses. Forty-four patients (50%) also had stable disease at their first 8-week assessment, and the median progression-free survival (PFS) was 100 days (95% CI, 58 to 140 days). Low hemoglobin and high alkaline phosphatase predicted for short PFS. The principal toxicity, an ...

Oral exposure to benzo[a]pyrene in the mouse: detoxication by inducible cytochrome P450 is more important than metabolic activation.

Abstract: The cytochrome P450 (CYP1A1) enzyme metabolically activates many polycyclic aromatic hydrocarbons, including benzo[a]pyrene (BaP), to DNA- and protein-binding intermediates that are associated with toxicity, mutagenesis, and carcinogenesis. As a result, it is widely accepted that CYP1A1 potentiates the toxicity of this class of chemicals. In distinct contrast, we show here that CYP1A1 inducibility is essential in the detoxication of oral BaP. We compared Cyp1a1(-/-) knockout mice, having the genetic absence of the CYP1A1 enzyme, with Cyp1a1(+/+) wild-type mice. At an oral BaP dose of 125 mg/kg/day, Cyp1a1(-/-) mice died within 30 days whereas Cyp1a1(+/+) mice displayed no outward signs of toxicity. The rate of BaP clearance was 4-fold slower in Cyp1a1(-/-) than Cyp1a1(+/+) mice. The cause of death in Cyp1a1(-/-) mice receiving oral BaP seemed to be immunotoxicity, including toxic chemical depression of the bone marrow; some toxic effects in Cyp1a1(-/-) mice were noted at a BaP dose as low as 1.25 mg/kg/day. DNA post-labeling studies demonstrated dramatically higher BaP-DNA adduct levels in all Cyp1a1(-/-) tissues assayed, with the exception of the small intestine, which is probably a major site of BaP metabolism in Cyp1a1(+/+) mice. Different BaP-DNA adduct patterns were also observed between the two genotypes receiving oral BaP. Despite previous studies in vitro and in cell culture that have shown a participatory role for CYP1A1 in BaP toxicity, the present data indicate that, in the intact animal, inducible CYP1A1 is extremely important in detoxication and protection against oral BaP toxicity.

Cadmium toxicity is reduced by nitric oxide in rice leaves

Abstract: We evaluate the protective effect of nitric oxide (NO) against Cadmium (Cd) toxicity in rice leaves. Cd toxicity of rice leaves was determined by the decrease of chlorophyll and protein contents. CdCl2 treatment resulted in (1) increase in Cd content, (2) induction of Cd toxicity, (3) increase in H2O2 and malondialdehyde (MDA) contents, (4) decrease in reduced form glutathione (GSH) and ascorbic acid (ASC) contents, and (5) increase in the specific activities of antioxidant enzymes (superoxide dismutase, glutathione reductase, ascorbate peroxidase, catalase, and peroxidase). NO donors [N-tert-butyl-α-phenylnitrone, 3-morpholinosydonimine, sodium nitroprusside (SNP), and ASC + NaNO2] were effective in reducing CdCl2-induced toxicity and CdCl2-increased MDA content. SNP prevented CdCl2-induced increase in the contents of H2O2 and MDA, decrease in the contents of GSH and ASC, and increase in the specific activities of antioxidant enzymes. SNP also prevented CdCl2-induced accumulation of NH4+, decrease in the activity of glutamine synthetase (GS), and increase in the specific activity of phenylalanine ammonia-lyase (PAL). The protective effect of SNP on CdCl2-induced toxicity, CdCl2-increased H2O2, NH4+, and MDA contents, CdCl2-decreased GSH and ASC, CdCl2-increased specific activities of antioxidant enzymes and PAL, and CdCl2-decreased activity of GS were reversed by 2-(4-carboxy-2-phenyl)-4,4,5,5-tetramethyl-imidazoline-1-oxyl-3-oxide, a NO scavenger, suggesting that protective effect by SNP is attributable to NO released. Reduction of CdCl2-induced toxicity by NO in rice leaves is most likely mediated through its ability to scavenge active oxygen species including H2O2.

Effects of 25 pharmaceutical compounds to Lemna gibba using a seven-day static-renewal test.

Abstract: Antibiotics are known to have antichloroplastic properties, but their effects on aquatic higher plants are virtually unknown. In order to address this issue, 25 pharmaceuticals, including 22 antibiotics, were assessed for phytotoxicity to the aquatic higher plant Lemna gibba. A 7-d static-renewal test was used, and plants were treated with 0, 10, 30, 100, 300, and 1,000 microg/L of pharmaceutical-containing growth media. Phytotoxicity was assessed using multiple growth and biochemical endpoints. Effective concentration (EC)50, EC25, and EC10 values as well as tests for significant differences between treatments and controls lowest-observed-effect concentration (LOECs) were calculated for each endpoint. Twelve different classes of antibiotics were assessed; however, only members of the fluoroquinolone, sulfonamide, and tetracycline classes of antibiotics displayed significant phytotoxicity. The most toxic members of each of these classes tested were lomefloxacin, sulfamethoxazole, and chlortetracycline, with wet weight EC25 values of 38, 37, and 114 microg/L, respectively. Injury symptoms were comparatively uniform and consistent among chemical classes while degree of phytotoxicity varied considerably. Both of these criteria varied markedly between classes. Wet mass was consistently the most sensitive endpoint above 100 microg/L; conversely, frond number was the most sensitive below 100 microg/L. Pigment endpoints were significantly less sensitive than growth endpoints.

The changing view of acrylamide neurotoxicity.

Abstract: Acrylamide (ACR) is a water-soluble, vinyl monomer that has multiple chemical and industrial applications: eg, waste water management, ore processing In addition, ACR is used extensively in molecular laboratories for gel chromatography and is present in certain foods that have been prepared at very high temperatures Extensive studies in rodents and other laboratory animals have provided evidence that exposure to monomeric ACR causes cellular damage in both the nervous and reproductive systems, and produces tumors in certain hormonally responsive tissues Whereas human epidemiological studies have demonstrated a significantly elevated incidence of neurotoxicity in occupationally exposed populations, such research has not, to date, revealed a corresponding increase in cancer risk Since the announcement by a Swedish research group in April 2002 [J Ag Food Chem 50 (2002) 4998] regarding the presence of ACR in potato and grain-based foods, there has been a renewed interest in the toxic actions of this chemical Therefore, in this review, we consider the different toxic effects of ACR The neurotoxic actions of ACR will be the focal point since neurotoxicity is a consequence of both human and laboratory animal exposure and since this area of investigation has received considerable attention over the past 30 years As will be discussed, a growing body of evidence now indicates that the nerve terminal is a primary site of ACR action and that inhibition of corresponding membrane-fusion processes impairs neurotransmitter release and promotes eventual degeneration The electrophilic nature of ACR suggests that this neurotoxicant adducts nucleophilic sulfhydryl groups on certain proteins that are critically involved in membrane fusion Adduction of thiol groups also might be common to the reproductive and carcinogenic effects of ACR A final goal of this review is to identify data gaps that retard a comprehensive understanding of ACR pathophysiological processes

Investigations into glyphosate-resistant horseweed (Conyza canadensis): retention, uptake, translocation, and metabolism

Abstract: The mechanism of glyphosate resistance in horseweed was investigated. Eleven biotypes of putative sensitive (S) and resistant (R) horseweed were obtained from regions across the United States and examined for foliar retention, absorption, translocation, and metabolism of glyphosate. Initial studies used spray application of 14C-glyphosate to simulate field application. When S and R biotypes were compared in the absence of toxicity at a sublethal dose, we observed comparable retention and absorption but reduced root translocation in the R biotypes. S and R biotypes from Delaware were further examined at field use rates and results confirmed similar retention and absorption but reduced root translocation in the R biotypes. Application of 14C-glyphosate to a single leaf demonstrated reduced export out of the treated leaf and lower glyphosate import into other leaves, the roots, and the crown in R relative to S biotypes. Examination of the treated leaf by autoradiography showed that glyphosate loadin...

Identification of putative gene based markers of renal toxicity.

Abstract: This study, designed and conducted as part of the International Life Sciences Institute working group on the Application of Genomics and Proteomics, examined the changes in the expression profile of genes associated with the administration of three different nephrotoxicants--cisplatin, gentamicin, and puromycin--to assess the usefulness of microarrays in the understanding of mechanism(s) of nephrotoxicity. Male Sprague-Dawley rats were treated with daily doses of puromycin (5-20 mg/kg/day for 21 days), gentamicin (2-240 mg/kg/day for 7 days), or a single dose of cisplatin (0.1-5 mg/kg). Groups of rats were sacrificed at various times after administration of these compounds for standard clinical chemistry, urine analysis, and histological evaluation of the kidney. RNA was extracted from the kidney for microarray analysis. Principal component analysis and gene expression-based clustering of compound effects confirmed sample separation based on dose, time, and degree of renal toxicity. In addition, analysis of the profile components revealed some novel changes in the expression of genes that appeared to be associated with injury in specific portions of the nephron and reflected the mechanism of action of these various nephrotoxicants. For example, although puromycin is thought to specifically promote injury of the podocytes in the glomerulus, the changes in gene expression after chronic exposure of this compound suggested a pattern similar to the known proximal tubular nephrotoxicants cisplatin and gentamicin; this prediction was confirmed histologically. We conclude that renal gene expression profiling coupled with analysis of classical end points affords promising opportunities to reveal potential new mechanistic markers of renal toxicity.

Acute toxicity after high-dose systemic injection of helper-dependent adenoviral vectors into nonhuman primates.

Abstract: Systemic intravascular delivery of adenoviral (Ad) vectors for liver-directed gene therapy has been widely employed because of its simplicity, noninvasiveness, and potential for high transduction. For first-generation Ad vectors (FGAd), this results in high but transient levels of transgene expression and long-term hepatotoxicity due to viral gene expression from the vector backbone. Furthermore, high doses also result in an acute innate inflammatory response with potentially lethal consequences. Unlike FGAd, helper-dependent Ad vectors (HDAd) contain no viral genes and can provide sustained, high-level transgene expression with negligible long-term toxicity. However, whether the absence of viral gene expression leads to any decrease of acute toxicity in nonhuman primates has yet to be determined. To address this, we injected one baboon with 5.6 x 10(12) HDAd viral particles (VP)/kg and a second with 1.1 x 10(13) VP/kg. Approximately 50% hepatocyte transduction, accompanied by mild and transient acute toxicity, was observed in the animal receiving the lower dose. In the animal receiving the higher dose, 100% hepatocyte transduction, accompanied by lethal acute toxicity, was observed. These results indicate that systemic delivery of HDAd, like FGAd, results in acute toxicity in baboons consistent with activation of the innate inflammatory response, the severity of which is dose dependent, and confirm the hypothesis that Ad-mediated acute toxicity is independent of viral gene expression.

Inhaled particles and lung cancer, part B: paradigms and risk assessment.

Abstract: Poorly soluble particles of low toxicity (PSP), such as CB, TiO2 and coal mine dust, have been demonstrated to cause lung cancer in rodents, being most pronounced in rats. Adequate epidemiologic studies do not clearly indicate increased lung cancer rates in humans exposed to such particles. This has caused controversial positions in regulatory decisions on PSP on different levels. The present review discusses the current paradigms in rodent particle carcinogenicity, i.e., (i) role of particle overload and of persistent inflammation and (ii) fibrosis as an intermediate step in particle-induced lung cancer with regard to human risk assessment. Fibrosis, which is usually considered a precursor of lung cancer in humans, was not related to lung tumors in an animal study using 6 different particles, each at 3 dosages. Lung tumors after both inhalation and intratracheal instillation of PSP are related to particle surface dose, which forwards hazard assessment at surface-based nonoverload concentrations and a standard setting using surface as an exposure metric. The scarce data available on humans do not support the overload concept but suggest a role for persistent lung inflammation. Differences in antioxidant protection between different rodent species correlate with susceptibility to PSP-induced carcinogenicity and support the need for detailed studies on antioxidant response in humans. Apart from such bridging studies, further focus is also needed on surface chemistry and modifications in relation to their adverse biologic effects. © 2004 Wiley-Liss, Inc.

Comparison of transfection agents in forming complexes with ferumoxides, cell labeling efficiency, and cellular viability

Abstract: By complexing ferumoxides or superparamagnetic iron oxide (SPIO) to transfection agents (TAs), it is possible to magnetically label mammalian cells. There has been no systematic study comparing TAs complexed to SPIO as far as cell labeling efficiency and viability. This study investigates the toxicity and labeling efficiency at various doses of FEs complexed to different TAs in mammalian cells. Different classes of TAs were used, such as polycationic amines, dendrimers, and lipid-based agents. Cellular toxicity was measured using doses of TAs from 1 to 50 microg/mL in incubation media. Iron incorporation efficiency was measured by combining various amounts of FEs and different doses of TAs. Lipofectamine2000 showed toxicity at lowest dose (1 microg/mL), whereas FuGENE6 and low molecular weight poly-L-lysine (PLL) showed the least toxicity. SPIO labeling efficiency was similar with high-molecular-weight PLL (388.1 kDa) and superfect, whereas FuGENE6 and low-molecular-weight PLL were inefficient in labeling cells. Concentrations of 25 to 50 microg/mL of FEs complexed to TAs in media resulted in sufficient endocytosis of the SPIO into endosomes to detect cells on cellular magnetic resonance imaging.

Aminoglycoside toxicity: daily versus thrice-weekly dosing for treatment of mycobacterial diseases.

Abstract: Aminoglycoside use is limited by ototoxicity and nephrotoxicity. This study compared the incidences of toxicities associated with 2 recommended dosing regimens. Eighty-seven patients with tuberculosis or nontuberculous mycobacterial infections were prospectively randomized by drug to receive 15 mg/kg per day or 25 mg/kg 3 times per week of intravenous streptomycin, kanamycin, or amikacin. Doses were adjusted to achieve target serum concentrations. The size of the dosage and the frequency of administration were not associated with the incidences of ototoxicity (hearing loss determined by audiogram), vestibular toxicity (determined by the findings of a physical examination), or nephrotoxicity (determined by elevated serum creatinine levels). Risk of ototoxicity (found in 32 [37%] of the patients) was associated with older age and with a larger cumulative dose received. Vestibular toxicity (found in 8 [9%] of the patients) usually resolved, and nephrotoxicity (found in 13 [15%] of the patients) was mild and reversible in all cases. Subjective changes in hearing or balance did not correlate with objective findings. Streptomycin, kanamycin, and amikacin can be administered either daily or 3 times weekly without affecting the likelihood of toxicity.

A Phase I and pharmacological study of the platinum polymer AP5280 given as an intravenous infusion once every 3 weeks in patients with solid tumors.

Abstract: Purpose: This Phase I study was designed to determine the maximum tolerated dose, profile of adverse events, and dose-limiting toxicity of AP5280 in patients with solid tumors. Furthermore, the platinum (Pt) pharmacokinetics after AP5280 administration and preliminary antitumor activity were evaluated. AP5280 is a Pt agent linked to the water-soluble, biocompatible copolymer N -(2-hydroxypropyl)methacrylamide, which potentially increases Pt accumulation in tumors via the enhanced permeability and retention effect. In this way, it is anticipated that a higher activity of therapeutic Pt can be reached. The pharmaceutical product contains approximately 8.5% of Pt by weight and has a molecular weight of approximately 25,000. Experimental Design: Adult patients with solid tumors received AP5280 as a 1-h i.v. infusion every 21 days. Pharmacokinetics of total and unbound Pt were determined during the first treatment course and before the start of each new cycle using noncompartmental pharmacokinetic analysis. Pt-DNA adduct concentrations in WBCs and, if available, in tumor tissue were quantified using a sensitive 32 P postlabeling assay. Results: Twenty-nine patients were treated at eight dose levels (90–4500 mg Pt/m 2 ). The dose-limiting toxicity was Common Toxicity Criteria grade 3 vomiting and was experienced at 4500 mg Pt/m 2 in two of six patients. The maximum tolerated dose on this schedule was therefore 4500 mg Pt/m 2 , and the recommended dose for a Phase II study is 3300 mg Pt/m 2 . Renal toxicity and myelosuppression, toxicities typically observed with cisplatin and carboplatin, were minimal for AP5280. The area under the curve of total Pt increased with increasing AP5280 dose. Plasma clearance of total Pt was 644 ± 266 ml/h, and the terminal half-life was 116 ± 46.2 h. After AP5280 administration, Pt-guanine-guanine DNA adduct concentrations in WBCs ranged from 70 to 1848 amol/μg DNA, concentrations that were substantially lower than concentrations measured after administration of therapeutic doses of cisplatin. Conclusions: AP5280 can be administered safely as a 1-h i.v. infusion at a dose of 3300 mg Pt/m 2 once every 3 weeks and produces prolonged plasma exposure compared with any of the free Pt-containing drugs. However, it remains to be determined whether AP5280 can actually increase Pt delivery to the DNA of tumor cells in man as has been shown in experimental models.