Chemical research in toxicology
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Chem. Res. Toxicol. · Apr 2016
Examination of the Impact of Copper(II) α-(N)-Heterocyclic Thiosemicarbazone Complexes on DNA Topoisomerase IIα.
Type II DNA topoisomerases resolve topological knots and tangles in DNA that result from routine cellular processes and are effective targets for anticancer therapeutics. To this end, thiosemicarbazones have been identified as having the ability to kill cancer cells from several cell lines. Literature evidence suggests that at least some thiosemicarbazones have an impact on topoisomerase II activity. ⋯ This evidence is supported by the fact that both [Cu(APY-ETSC)Cl] and [Cu(APZ-MTSC)Cl], and to a lesser extent the ligands, inhibit topoisomerase IIα-mediated ATP hydrolysis. Based upon kinetic analysis, the Cu(II) complexes appear to be noncompetitive inhibitors of the ATPase domain of topoisomerase IIα. Taken together, our results provide evidence that Cu(II) complexes of α-(N)-heterocyclic thiosemicarbazones catalytically inhibit the enzyme through the ATPase domain but also promote double-stranded DNA cleavage by the enzyme.
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Chem. Res. Toxicol. · Aug 2015
Free-Base and Protonated Nicotine in Electronic Cigarette Liquids and Aerosols.
As with other tobacco aerosols, nicotine delivery from e-cigarettes (ECIG) depends on the total nicotine and its partitioning between free-base (Nic) and protonated (NicH(+)) forms. Previous studies of ECIG nicotine emissions have generally reported "nicotine yield" without attention to whether the methods employed resulted in quantification of the total nicotine or only one of its forms, making reported results difficult to compare across studies or to evaluate against reported blood exposure. ⋯ Apparent pH was found to correlate with nicotine partitioning and can provide a useful indirect measure when chromatography is unavailable. Finally, labeled ECIG liquid nicotine concentration in commercial products was often inconsistent with measured nicotine.
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Chem. Res. Toxicol. · Jul 2015
5'-O-Alkylpyridoxamines: Lipophilic Analogues of Pyridoxamine Are Potent Scavengers of 1,2-Dicarbonyls.
Pyridoxamine (PM) is a prospective drug for the treatment of diabetic complications. In order to make zwitterionic PM more lipophilic and improve its tissue distribution, PM derivatives containing medium length alkyl groups on the hydroxymethyl side chain were prepared. The synthesis of these alkylpyridoxamines (alkyl-PMs) starting from pyridoxine offers high yields and is amenable to bulk preparations. ⋯ Alkyl-PMs in the presence of MGO also protected the enzymatic activity of lysozyme that contains several arginine residues next to its active site. Alkyl-PMs can be expected to trap MGO and other toxic 1,2-carbonyl compounds more effectively than PM, especially in lipophilic tissue environments, thus protecting macromolecules from functional damage. This suggests potential therapeutic uses for alkyl-PMs in diabetes and other diseases characterized by the elevated levels of toxic dicarbonyl compounds.
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Chem. Res. Toxicol. · Jan 2015
ReviewPyrrolizidine Alkaloids: Potential Role in the Etiology of Cancers, Pulmonary Hypertension, Congenital Anomalies, and Liver Disease.
Large outbreaks of acute food-related poisoning, characterized by hepatic sinusoidal obstruction syndrome, hemorrhagic necrosis, and rapid liver failure, occur on a regular basis in some countries. They are caused by 1,2-dehydropyrrolizidine alkaloids contaminating locally grown grain. Similar acute poisoning can also result from deliberate or accidental consumption of 1,2-dehydropyrrolizidine alkaloid-containing herbal medicines, teas, and spices. ⋯ However, these alkaloids are genotoxic and can cause slowly developing chronic diseases such as pulmonary arterial hypertension, cancers, cirrhosis, and congenital anomalies, conditions unlikely to be easily linked with dietary exposure to 1,2-dehydropyrrolizidine alkaloids, especially if clinicians are unaware that such dietary exposure is occurring. This Perspective provides a comprehensive review of the acute and chronic toxicity of 1,2-dehydropyrrolizidine alkaloids and their potential to initiate certain chronic diseases, and suggests some associative considerations or indicators to assist in recognizing specific cases of diseases that may have resulted from dietary exposure to these hazardous natural substances. If it can be established that low-level dietary exposure to 1,2-dehydropyrrolizidine alkaloids is a significant cause of some of these costly and debilitating diseases, then this should lead to initiatives to reduce the level of these alkaloids in the food chain.
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Chem. Res. Toxicol. · May 2013
Comparative StudyComparison of the relative propensities of isoamyl nitrite and sodium nitrite to ameliorate acute cyanide poisoning in mice and a novel antidotal effect arising from anesthetics.
Isoamyl nitrite has previously been considered acceptable as an inhaled cyanide antidote; therefore, the antidotal utility of this organic nitrite compared with sodium nitrite was investigated. To facilitate a quantitative comparison, doses of both sodium nitrite and isoamyl nitrite were given intraperitoneally in equimolar amounts to sublethally cyanide-challenged mice. Righting recovery from the knockdown state was clearly compromised in the isoamyl nitrite-treated animals, the effect being attributable to the toxicity of the isoamyl alchol produced during hydrolysis of the isoamyl nitrite to release nitrite anion. ⋯ It is argued that administration of an effective inhaled aqueous sodium nitrite dose in humans is possible, though just beyond the capability of current individual metered-dose inhaler designs, such as those used for asthma. Finally, working at slightly greater than LD50 NaCN doses, it was fortuitously discovered that (i) anesthesia leads to significantly prolonged survival compared to that of unanesthetized animals and that (ii) the antidotal activity of nitrite anion was completely abolished under anesthesia. Plausible explanations for these effects in mice and their practical consequences in relation to testing putative cyanide antidotes are discussed.