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The interaction between phosphorothionate insecticides, pneumotoxic trialkyl phosphorothiolates and effects on lung
Abstract:
A number of phosphorothionate (P = S) insecticides, including bromophos and fenitrothion, prevent trialkyl phosphorothiolate (P = O)-induced lung toxicity and the resulting increase in lung weight normally observed at 3 days in the rat. Measurement of 7-ethoxycoumarin O-deethylase (7-EC) activity after both phosphorothionate and phosphorothiolate dosing revealed differing patterns of loss of enzyme activity. Depletion of 7-EC activity by phosphorothionates was maximal between 2 and 10 h after dosing, with recovery between 24 and 72 h. Phosphorothiolates, however, appear to cause two phases of loss of 7-EC activity, an initial fall of approximately 30% observed at 2 h and a secondary fall, maximal on day 3, with loss of 97% of activity, apparently associated with the pathological changes in the lung. It is suggested that oxidative metabolism of phosphorothionates known to occur at the P = S moiety, with suicidal loss of P-450, may then prevent oxidative activation of an S-methyl on the phosphorothiolates, the most likely site for production of a reactive intermediate capable of damaging the lung. Lung 7-EC in rat is sensitive to concentrations of the phosphorothionates bromophos and fenitrothion at 5-25 times less than those causing loss of liver 7-EC activity and at doses 125-600 times less than their LD50s. If repeated in man this may have implications for personnel occupationally exposed to these compounds.
Insights
Certain phosphorothionate insecticides protect rats from lung toxicity caused by phosphorothiolates. This protection involves differential effects on 7-ethoxycoumarin O-deethylase (7-EC) enzyme activity in the lung.
Area of Science:
- Toxicology
- Biochemistry
- Pharmacology
Background:
- Phosphorothionate (P=S) insecticides, like bromophos and fenitrothion, are known to cause lung toxicity.
- Trialkyl phosphorothiolate (P=O) compounds induce lung toxicity and increased lung weight in rats.
- 7-ethoxycoumarin O-deethylase (7-EC) is an enzyme sensitive to insecticide exposure.
Purpose of the Study:
- To investigate the protective effects of phosphorothionate insecticides against phosphorothiolate-induced lung toxicity.
- To compare the impact of phosphorothionates and phosphorothiolates on 7-EC activity in rat lungs and livers.
- To elucidate the mechanism by which phosphorothionates mitigate lung damage.
Main Methods:
- Administration of phosphorothionate and phosphorothiolate insecticides to rats.
- Measurement of 7-ethoxycoumarin O-deethylase (7-EC) activity in lung and liver tissues at various time points.
- Assessment of lung weight and pathological changes.
Main Results:
- Phosphorothionates prevented phosphorothiolate-induced lung toxicity and weight gain.
- Phosphorothionates caused a transient loss of 7-EC activity (2-10h) with recovery, while phosphorothiolates induced a biphasic loss, with a significant secondary decrease (97%) by day 3.
- Lung 7-EC was more sensitive to bromophos and fenitrothion than liver 7-EC, at doses significantly lower than their LD50s.
Conclusions:
- Oxidative metabolism of the P=S moiety in phosphorothionates may lead to P-450 inactivation, preventing the oxidative activation of phosphorothiolates responsible for lung damage.
- The differential effects on 7-EC activity suggest distinct mechanisms of toxicity and protection.
- The high sensitivity of lung 7-EC to these insecticides may have implications for occupational exposure in humans.