The Modification of Histidine Residues
Roger L. Lundblad in Chemical Reagents for Protein Modification, 2020
Another example of the modification of histidine by reagents which, in general, react more avidly with other residues is the reaction of d-amino acid oxidase with dansyl chloride.26 In this study, d-amino acid oxidase was allowed to react with a fivefold molar excess of dansyl chloride (from a stock solution in acetone; final concentration of acetone in the reaction mixture did not exceed 5% final volume) in 0.05 M phosphate, pH 6.6. The reaction was terminated by the addition of benzoate, insoluble material removed by centrifugation, and the mixture passed through a G-25 column equilibrated with 0.06 M phosphate, 0.010 M benzoate, pH 6.6. Reaction with dansyl chloride under these conditions resulted in virtually complete inactivation of the enzyme with the incorporation of 1.7 mol of reagent/mol enzyme. Substantially complete reactivation occurred with 0.5 M hydroxylamine (NH2OH) at pH 6.6. This reactivation excluded reaction with primary amino functional groups such as lysine, and amino acid analysis suggested the reaction had not occurred with an oxygen nucleophile such as tyrosine. Treatment of the enzyme with diethylpyrocarbonate also resulted in the loss of catalytic activity and reduced the amount of dansyl groups incorporated in a subsequent reaction suggesting that dansyl chloride reacts with the same functional group that reacted with diethylpyrocarbonate.
Acute Toxicity Testing by the Dermal Route
Rhoda G. M. Wang, James B. Knaak, Howard I. Maibach in Health Risk Assessment, 2017
In humans, absorption of a topical dose of hydrocortisone increased from 0.456% of applied dose to 4.48% after occlusion of the dose site.39 The absorption of cinnamic acid through monkey skin, expressed as percentage of applied dose, rose from 38.6 to 83.9% when the dermal surface was occluded.40 There was a similar increase from 17.8 to 60.8% in absorption through human skin (in vitro). In the rabbit (commonly used for dermal toxicity testing), one study41 showed that 1.0 g/kg of hydroxylamine sulfate was not lethal to animals when the treated skin was covered with only gauze dressing. However, occlusion with plastic resulted in death of 90% of rabbits receiving one half of the this dose. It should be noted that absorption may not be enhanced by occlusion for every chemical.42
Dapsone
M. Lindsay Grayson, Sara E. Cosgrove, Suzanne M. Crowe, M. Lindsay Grayson, William Hope, James S. McCarthy, John Mills, Johan W. Mouton, David L. Paterson in Kucers’ The Use of Antibiotics, 2017
Patients taking dapsone are subject to both dose-dependent toxicity and idiosyncratic reactions. In general, many millions of patients with leprosy have been successfully treated with dapsone with little, if any, problem with adverse effects, largely because the dose that is required is lower than the dose at which dose-dependent toxicity becomes problematic. When plasma levels remain below 5 µg/ml, dose-dependent toxicity is unlikely (Zuidema et al., 1986); however, when it rises above that level, hematologic problems such as methemoglobinemia begin to rise in incidence. The mechanism of dose-dependent toxicity is thought to be mediated by the hydroxylamine metabolite. Hypersensitivity reactions to dapsone have recently been reviewed, with epidemiologic studies suggesting a prevalence rate of 1.4% (95% confidence interval [CI]: 1.2–1.7%) (Lorenz et al., 2012).
Dapsone-induced methemoglobinemia and hemolysis in a woman without G6PD deficiency presenting with idiopathic urticaria
Published in Hematology, 2022
Yang Hu, Mimansa Geere, Maham Awan, Andrew D. Leavitt, Laura E. Brown, Hadley J. Pearson, Jocelyn S. Gandelman, Scott C. Kogan
The ‘bite cell’ is an aberrant feature of mature red blood cells seen on peripheral smear characterized by removal of one or more portions of the biconcave disc rim of red blood cells by splenic macrophages at sites where hemoglobin has been abnormally deposited [1]. Occasionally, ‘blister cells’, which have a large vacuole along the periphery, may also form alongside ‘bite cells.’ Oxidative injury of red blood cells can result in hemoglobin sulfhydryl group oxidation, which can precipitate the formation of these abnormal red blood cell features. They are most commonly associated with hemolysis and methemoglobinemia in patients with G6PD deficiency exposed to triggers such as medications including dapsone [14,15]. Dapsone is a sulfone antibiotic used as first line therapy for leprosy and second line therapy for Pneumocystis pneumonia [16]. It can also be used as a second line therapy for chronic spontaneous urticaria [2,17]. Dapsone is converted to the metabolite hydroxylamine, which can accumulate in red blood cells and generate free radicals that deplete glutathione stores, leading to oxidative damage of the red blood cell membrane [18]. G6PD is a key enzyme that participates in restoring glutathione. In the rare case of dapsone overdose, hydroxylamine can accumulate to excess levels to overwhelm the protective effect of glutathione and cause oxidative damage to red blood cells even in the presence of normal G6PD levels [11].
What are the immunopharmacological effects of furazolidone? A systematic review
Published in Immunopharmacology and Immunotoxicology, 2021
Ivan Brito Feitosa, Bruno Mori, Ana Paula de Azevedo dos Santos, Janaína Cecília Oliveira Villanova, Carolina Bioni Garcia Teles, Allyson Guimarães Costa
Nonetheless, furazolidone’s metabolism and cytotoxic mechanisms may vary between different types of cells with different metabolic capacities, and its cytotoxicity is not attributed to a single toxic intermediate [7,8]. Its activity spectra are related to the reducing potential of its 5-nitro group, which is between 250 and 270 mV. Nitroreduction, on the other hand, occurs through type I or II reduction of the nitro group in the presence of parasitic NADPH-cytochrome P450 reductases. Under anaerobic conditions, type I NTRs catalyze the reduction of nitrofurans (NFs) to produce anti-pathogenic hydroxylamine. Under aerobic conditions, nitroreduction, catalyzed by type II NTRs, produces reactive oxygen and nitrogen species (ROS/RNS), causing oxidative stress to pathogens and ultimately death [9].
Hybrid inhibitors of DNA and HDACs remarkably enhance cytotoxicity in leukaemia cells
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2020
Yoojin Song, Sun You Park, Zhexue Wu, Kwang-Hyeon Liu, Young Ho Seo
Hydroxylamine hydrochloride (2.25 g, 32.44 mmol) in methanol (5 ml) was added to a solution of potassium hydroxide (1.82 g, 32.44 mmol) in methanol (5 ml) at 0 °C. The mixture was stirred for 15 min at 0 °C and the precipitated potassium chloride was removed and the filtrate was used as such; To a solution of the compound 6b (0.20 g, 0.72 mmol) in tetrahydrofuran (10 ml) was added to freshly prepared hydroxylamine at 0 °C and stirred at the same temperature for 2 h. The mixture was neutralised with acetic acid to pH 7 and extracted with ethyl acetate. The organic layer was dried over Na2SO4, concentrated under reduced pressure and purified by MPLC (Biotage SNAP KP-C18 column) to afford compound 8b in 46% yield. Rf = 0.27 (6:4 ethyl acetate: hexanes). 1H NMR (500 MHz, CDCl3) δ 6.98 (d, J=8.5 Hz, 2 H), 6.57 (d, J=8.5 Hz, 2 H), 3.20 (t, J=7.5 Hz, 4 H), 2.50 (t, J=7.5 Hz, 2 H), 2.12–2.06 (m, 2 H), 1.92 (m, 2 H), 1.63–1.55 (m, 4 H), 0.92 (t, J=7.5 Hz, 6 H). 13 C NMR (125 MHz, CDCl3) δ 172.0, 146.7, 129.3, 127.7, 112.1, 53.1, 33.9, 32.3, 27.2, 20.5, 11.6. ESI MS (m/z) 279.20 [M + 1]+.
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