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OXPRION Résumé de rapport

Project ID: QLG3-CT-2002-81871
Financé au titre de: FP5-LIFE QUALITY
Pays: Italy

Obtention and evaluation of an oxydative stress in mice by dimethoate treatment

In order to determine the amount of dimethoate to use, mice were treated with different amount of the drug for different times. 1 week treatments with 10 and 30 mg/kg of dimethoate let to see as tissues (livers) reacted to the external insult activating the antioxidant detoxifying enzymatic systems.All the dosed enzyme increased their specific activities (SOD, catalase, glutathione transferase-GST, reductase-GSSGRx-, peroxidase GSHPx): an acute stress was observed in terms of amount of carbonyls in proteins. This acute response indicated a tissues positive response to the stress not sufficient to detoxifying all ROS (reactive oxygen species).

Longer treatments (4 and 5 weeks) with 10 mg/kg of dimethoate had a different effects on enzymatic activities. At 4 weeks levels of enzymes tended to stabilize and to return to blank levels: the enzymatic systems did not tend to counteract drug action, in fact carbonyls were higher in treated mice than in blanks (not treated). 5 weeks treatment with 10 mg/kg or 30 mg/kg of dimethoate resulted in more marked decrease in enzymatic activities: only catalase level seemed to be higher but it was not enough to counteract oxidative stress as demonstrated by protein carbonyls that were always higher than blank levels. GSH Px activity was very low: this activity is important in all tissues in detoxifying organic peroxides (Se-independent activity).

Ratio GSHPx/SOD was very low during dimethoate treatments indicating an inefficient antioxidant capability of tissues. 60 and 100 mg/kg of dimethoate treatments were very toxic and therefore were excluded for further experiments. These results can be combined to evaluation of glutathione (GSH), GSH/GSSG ratio and total GSH (=[GSH] + 2x[GSSG]).

One week treatment with 10 or 30 mg/kg of dimethoate resulted in small decreases in the GSH/GSSG ratio, due to higher GSSG levels, and no significant changes in total GSH levels was observed. A decrease in GSH/GSSG ratio was evident with 30 mg/kg. An oxidative stress situation is apparent (expecially at 30 mg/kg), with small oxidative damages (confirmed by protein carbonyls dosage): animal resist an acute oxidative stress with their enzyme equipment. Five week treatment with 10 or 30 mg/kg does not change dramatically the monitored parameters: GSH/GSSG ratios stabilize to a lower level (with decrements of 20-35%), small increases in carbonyl content are observed; the total GSH becomes lower with 30 mg/kg dimethoate, a sign that dimethoate is actively detoxicated. Animals reach a new "steady state" (see enzyme activities results) and resist the oxidative stress with apparently small damages. Treatment, for one or five weeks, with the intermediate doses of 15 mg/kg dimethoate confirms these results: an oxidative stress status is established and mice adapt their metabolism to this new situation.

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Giuseppina PITARI, (professor)
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