Identification of mechanisms involved in the acute airway toxicity inducedby parathion

Organophosphates are still widely used worldwide and cause thousands of int oxications every year. In this work we investigated the mechanisms of parat hion (Pth) airway toxicity, using biochemical and functional approaches. A plethysmographic technique for unrestrained guinea pigs was used to analyze Pth-induced modifications of airway mechanics and responsiveness to acetyl choline (ACh; 0.1-3.2 mg/ml, 2-min inhalation each dose). The isolated perf used rabbit lung preparation was used to study the acute effects of Pth on airway responsiveness to ACh (10(-8)-10(-3) M), histamine (10(-8)-10(-3) M) and substance P (10(-10)-10(-6) M), pulmonary acetylcholinesterase inhibit ion and cytochrome P450 (P450) activity. and their modifications with previ ous administration of Pth (1 mg/kg s.c. daily, 7 days). We found that: (1) In guinea pigs Pth (3.2-17 mg/kg i.p.) produced a dose-dependent increase i n a lung resistance index (iRL), which was greatly reverted (similar to 50% ) by salbutamol (2 mg/ml, 2-min inhalation, or 10 mu g/kg i.p.). This salbu tamol effect was transient (5-10 min), suggesting that this bronchodilator triggered additional obstructive mechanisms. (2) Pth increased the water co ntent in lung parenchyma samples, but not in trachea or bronchi, and augmen ted the respiratory secretions measured through monosaccharide content in b ronchoalveolar lavage. (3) The increase in iRL was greater in female animal s, probably due to a higher P450 basal activity, and completely blocked by pharmacological inhibition of P450 with piperonyl butoxide (500 mg/kg i.p.) . (4) In male guinea pigs a subclinical dose of Pth (10 mg/kg i.p.) induced ah-way hyperresponsiveness to ACh. In isolated perfused rabbit lung Pth (1 0(-6) M) produced airway hyperresponsiveness to ACh and histamine, the latt er prevented by atropine (10(-5) M). (5) Repetitive exposure to subclinical doses (1 mg/kg s.c.) of Pth during 1 week caused similar to 80% inhibition of P450 activity in rabbits, which was not enough, however, to prevent the functional manifestation of Pth toxicity in the airways.