Identification of mechanisms involved in the acute airway toxicity induced by parathion

Organophosphates are still widely used worldwide and cause thousands of intoxications every year. In this work we investigated the mechanisms of parathion (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 acetylcholine (ACh: 0.1-3.2 mg/ml, 2-min inhalation each dose). The isolated perfused 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 inhibition and cytochrome P450 (P450) activity, and their modifications with previous 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 in a lung resistance index (iRL), which was greatly reverted (approximately 50%) by salbutamol (2 mg/ml, 2-min inhalation, or 10 microg/kg i.p.). This salbutamol effect was transient (5-10 min), suggesting that this bronchodilator triggered additional obstructive mechanisms. (2) Pth increased the water content in lung parenchyma samples, but not in trachea or bronchi, and augmented the respiratory secretions measured through monosaccharide content in bronchoalveolar lavage. (3) The increase in iRL was greater in female animals, 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 airway hyperresponsiveness to ACh. In isolated perfused rabbit lung Pth (10(-6) M) produced airway hyperresponsiveness to ACh and histamine, the latter prevented by atropine (10(-5) M). (5) Repetitive exposure to subclinical doses (1 mg/kg s.c.) of Pth during 1 week caused approximately 80% inhibition of P450 activity in rabbits, which was not enough, however, to prevent the functional manifestation of Pth toxicity in the airways.