Add time:07/22/2019         Source:sciencedirect.com

The cellular reduction of 2-nitroimidazoles under hypoxic conditions can lead to cell killing. One of the postulated toxic intermediates is the two-electron reduction product, the nitrosoimidazole. 1-methyl-2-nitrosoimidazole (cas 116169-87-0) (INO) was used as a model to study the reactivity of 2-nitrosoimidazoles with sulfhydryls. INO reacted within minutes with bovine serum albumin (BSA) in a stoichiometric fashion as measured by the loss of its characteristic absorption at 360 nm. It appeared to react specifically with the SH group of BSA as demonstrated by the loss of 5,5′-dithiobis-2-nitrobenzoic acid (DTNB) reactive groups and by the loss of INO reactivity if BSA was previously reacted with DTNB. INO also depleted glutathione (GSH) and protein sulfhydryls (Pr-SH) in Chinese hamster ovary (CHO) cells in a concentration-dependent fashion. INO at 25 μM, a non-toxic concentration in terms of cell colony forming ability, depleted GSH to 10–20% of control levels within 5 min after treatment. Pr-SH were depleted more slowly to 60% of control levels. GSH recovered to near control levels over 3–4 hr but Pr-SH remained depressed. The recovery of GSH was blocked by buthionine sulfoximine (BSO), suggesting that the recovery was due to de novo synthesis of GSH. At a toxic concentration of INO (45 μM), GSH was again depleted to 10−20% and Pr-SH to 50% of control levels. No recovery of either was observed up to 4hr. The effect of this extensive oxidative stress on intracellular calcium (Ca2+i) levels was monitored using 1-[2-amino-5-(6-carboxyindole-2-yl)-phenoxy]-2-(2′-amino-5′-methylphenoxy)-ethane-N, N,N′,N′-tetraacetic acid pentaacetoxy methylester (INDO-1 AM). At toxic concentrations of INO, Ca2+i increased in a sustained, non-physiological manner starting at approximately 60 min after the addition of INO. No increase in Ca2+i was observed when cells were treated with non-toxic concentrations of INO. INO toxicity may be modulated by an uncontrolled influx of Ca2+ which can trigger the activation of cellular enzymes and lead to cell death.

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