methyl-linoleate-ozonide and cumene-hydroperoxide

In an in vitro study a comparison was made between the cytotoxicities of a model ozonide, methyl linoleate-9,10-ozonide (MLO), and a model peroxidative agent, cumene hydroperoxide (CumOOH), by measuring the effects of both compounds on the phagocytosing capacity of rat alveolar macrophages. Toxicity as well as detoxication characteristics of the ozonide were found to be similar to those of ozone: (1) vitamin E protected the alveolar macrophages in vitro against the ozonide, (2) glutathione (GSH) depletion enhanced the sensitivity of the cells towards the ozonide and (3) the ozonide did not enhance lipid peroxidation. This also suggests that GSH depletion, followed by lipid peroxidation, does not underlie the MLO toxicity. This was supported by the differences in protection provided by vitamin C, vitamin E and GSH. Supplementation of the macrophages with vitamin C resulted in a decrease in their sensitivity towards MLO and an increase in their sensitivity towards CumOOH. Following GSH depletion the sensitivity of the cells towards CumOOH had increased more than that towards MLO. Exposure to CumOOH led to a more extensive vitamin E depletion. The results of an in vivo study on the toxicity of MLO (in the rat) largely confirmed the findings of the in vitro study: partial contributions of vitamin E and the glutathione system to the protection against MLO.

Topics: Animals; Antioxidants; Benzene Derivatives; Glutathione; Linoleic Acids; Lipid Peroxidation; Lung Diseases; Macrophages, Alveolar; Ozone; Phagocytosis; Rats

In the present study the in vitro toxicities of methyl linoleate-9,10-ozonide (MLO) and cumene hydroperoxide (CumOOH), a model peroxidative agent, are compared. This was carried out using the inhibition of alveolar macrophage phagocytosis as an assessment of in vitro toxicity. Both agents, MLO and CumOOH caused a dose-dependent decrease in the phagocytosing activity of alveolar macrophages isolated from rat lungs. MLO was found to be three times more toxic than CumOOH. Supplementation of macrophages with vitamin C resulted in a decrease of their sensitivity towards MLO and an increase of their sensitivity towards CumOOH, suggesting that different mechanisms underlie the toxic effects of the compounds concerned. This was supported by the data on GSH and vitamin E depletion. In both cases, depletion of the antioxidant was more extensive on exposure to CumOOH. In addition, following GSH depletion, the sensitivity of the macrophages towards CumOOH was more increased than towards MLO. Further, MLO was not able to enhance the peroxide formation from methyl linoleate (ML), whereas CumOOH initiated the peroxide formation of ML. The results of ESR spin trap experiments further supported that MLO-induced toxicity is independent of lipid peroxidation. From all this it is concluded that both mechanisms known to be of importance for peroxide-induced cell toxicity, i.e., depletion of cellular GSH levels and/or lipid peroxidation are not the main processes causing MLO toxicity in vitro.

Topics: Animals; Antioxidants; Benzene Derivatives; Drug Synergism; Female; Free Radicals; In Vitro Techniques; Linoleic Acids; Lipid Peroxidation; Macrophages, Alveolar; Phagocytosis; Rats; Rats, Inbred Strains