Ultrastructural Effects of Phosphorothionates and other Inhibitors of Lung Monooxygenases: Protection against Trialkylphosphorothiolate-Induced Lung Injury

Abstract

An oral dose (25 mg/kg) of 0,0,S-triethylphosphorothiolate (OOSEtO) to rats results in selective injury of type I pneumocytes, degranulation of Clara cells, and pronounced increase in lung weight. A dose (12.5 mg/kg) of the related compound O,O,S-trimethylphosphorothionate (OOSMeS) causes neither injury nor degranulation but, when administered 2 h before OOSEtO (25 mg/kg), protects against all the signs of lung injury that would otherwise result from this dose of the compound. The administration of OOSMeS also results in the formation of large, electron-lucent granules within the apical cytoplasm of the Clara cells. The granules are not birefringent, and histochemical procedures indicate that they do not contain carbohydrate but may consist of lipid accumulated around a proteinaceous core. Similar granules are also observed after administration ofp-xylene, pseudocumene, and the pesticide bromophos. These compounds, like OOSMeS, inhibit 7-ethoxycoumarin O-deethylase activity in the lung and are capable of protecting against trialkylphosphorothiolate toxicity. This inhibition of 7-ethoxycoumarin O-deethylase activity suggests loss of pulmonary cytochrome P-450. This loss may account for both the protective action of these compounds and the formation of abnormal granules within Clara cells.