Toxicology and applied pharmacology
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Toxicol. Appl. Pharmacol. · Jan 2002
In vitro effects of organophosphorus anticholinesterases on muscarinic receptor-mediated inhibition of acetylcholine release in rat striatum.
The aim of the present study was to evaluate the in vitro modulation of muscarinic autoreceptor function by the organophosphorus (OP) anticholinesterases chlorpyrifos oxon, paraoxon, and methyl paraoxon. Acetylcholine (ACh) release was studied by preloading slices from rat striatum with [3H]choline and depolarizing with potassium (20 mM) in perfusion buffer containing hemicholinium-3 (to prevent reuptake of radiolabeled choline). Under these conditions, chlorpyrifos oxon, paraoxon, and methyl paraoxon (0.1-10 microM) all reduced ACh release in a concentration-dependent manner. ⋯ Together, the results suggest that chlorpyrifos oxon, paraoxon, and methyl paraoxon can activate muscarinic autoreceptors indirectly through inhibition of AChE. Both paraoxon and methyl paraoxon also directly activate whereas chlorpyrifos oxon blocks muscarinic autoreceptor function. Qualitative differences in the direct actions of these oxons at this presynaptic regulatory site could contribute to differential toxicity with high-dose exposures.
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Toxicol. Appl. Pharmacol. · Sep 2001
Comparative StudySpecies and regional variations in the effectiveness of antivenom against the in vitro neurotoxicity of death adder (Acanthophis) venoms.
Although viperlike in appearance and habit, death adders belong to the Elapidae family of snakes. Systemic envenomation represents a serious medical problem with antivenom, which is raised against Acanthophis antarcticus venom, representing the primary treatment. This study focused on the major Acanthophis variants from Australia and islands in the Indo-Pacific region. ⋯ Death adder venoms, including those from A. antarcticus geographic variants, differed not only in their venom composition but also in their neurotoxic activity and susceptibility to antivenom. For the first time toxicological aspects of A. hawkei, A. wellsi, A. rugosus, and A. sp. Seram venoms were studied.
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Toxicol. Appl. Pharmacol. · Sep 2001
Increased oxidative stress in dimethylnitrosamine-induced liver fibrosis in the rat: effect of N-acetylcysteine and interferon-alpha.
Oxidative stress may represent a common link between chronic liver damage and hepatic fibrosis. Antioxidants and interferon seem to protect against hepatic stellate cell (HSC) activation and liver fibrosis. This study evaluated (1) the effect of the profibrotic agent dimethylnitrosamine (DMN) on the hepatic oxidative balance in the rat; (2) the role played by the antioxidant agent N-acetylcysteine (NAC); and (3) the antifibrotic effects of two different types of interferon-alpha: recombinant alpha-2b (rIFN-alpha) and leukocyte alpha (LeIFN-alpha). ⋯ Administration of IFN-alpha exerted different effects according to the type used. Both IFNs decreased FN deposition; however, LeIFN-alpha significantly improved histology and oxidative parameters compared to those of untreated DMN and rats treated with rIFN-alpha. This study shows the role of free radicals in this model of hepatic fibrosis; the protective effect of NAC against liver fibrosis; and the antifibrotic effect exerted by IFN-alpha (particularly LeIFN-alpha) independent of its antiviral activity.
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Toxicol. Appl. Pharmacol. · Jun 2001
Mercuric ion attenuates nuclear factor-kappaB activation and DNA binding in normal rat kidney epithelial cells: implications for mercury-induced nephrotoxicity.
Mercuric ion (Hg(2+)), one of the strongest thiol-binding agents known, mediates the toxicity associated with elemental, inorganic, and organic mercurial compounds. Studies of cellular events associated with Hg(2+) toxicity have focused largely on disruption of cell membranes and impairment of mitochondrial functions. In contrast, few studies have sought to define the specific molecular mechanisms through which Hg(2+) might affect toxicity via alteration of thiol-dependent signal transduction pathways that regulate cell proliferation and survival. ⋯ Finally, Hg(2+) at concentrations as low as 5 microM significantly diminished NF-kappaB-mediated transcriptional activity when administered to kidney cells transiently transfected with an NF-kappaB-driven luciferase reporter gene (pLuc-4xNF-kappaB) prior to LPS treatment. These findings demonstrate that Hg(2+), at low cellular concentrations, attenuates NF-kappaB activation at sites associated with IkappaBalpha phosphorylation and degradation, nuclear translocation of the p50p65 heterodimer, and association of p50-cys(62) with the DNA kappaB binding site. Attenuation of NF-kappaB activation by Hg(2+) through these mechanisms may underlie apoptotic or other cytotoxic responses that are known to be associated with low level Hg(2+) exposure in kidney epithelial cells.
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Toxicol. Appl. Pharmacol. · Sep 2000
Comparative StudyOvotoxicity in female Fischer rats and B6 mice induced by low-dose exposure to three polycyclic aromatic hydrocarbons: comparison through calculation of an ovotoxic index.
Extensive destruction of primordial follicles by exposure to ovarian toxicants can cause early menopause in women. Primordial follicle destruction is known to result from dosing of mice and rats with three polycyclic aromatic hydrocarbons (PAHs), contaminants commonly found in cigarette smoke. Therefore, the purpose of this study was to compare relative ovotoxicity in mice and rats using the PAHs, 9, 10-dimethylbenzanthracene (DMBA), 3-methylcholanthrene (3-MC), and benzo[a]pyrene (BaP). ⋯ Calculation of the OI in mice and rats represents a method for comparing the relative potential risk of a variety of chemicals that produce ovarian damage at low levels following repeated exposures. The results also demonstrate that low-dose repeated exposures are substantially more toxic to the ovary than a single high-dose exposure. This finding is particularly important in view of the implications for chronic low-dose exposures of women to environmental chemicals.