Mechanism of protection against pneumotoxicity caused by O,S,S-trimethyl phosphorodithioate.

Abstract

O,S,S-Trimethyl phosphorodithioate (OSS-TMP) is a pneumotoxic impurity present in various organophosphorus insecticides. It produces morphological alteration of bronchiolar epithelial Clara cells accompanied by an increase in relative wet weight of the lung and severe body weight loss in rats. The present investigation demonstrates that rats pretreated with small doses of OSS-TMP develop a tolerance against body weight loss caused by a large dose of the compound. Pretreatment for three to four days gave better protection than that of one to two days with a concomitant decrease in relative lung weight to control level, although the protective effect against morphological change in lung parenchyma was not as striking; all the pretreatment regimens (one to four days) gave similar and rather moderate protection. Microsomal enzyme activities were measured in order to examine a possible biochemical mechanism of tolerance, and it was found that the small multiple doses of OSS-TMP for three and four days decreased arylhydrocarbon hydroxylase activity in liver and lung. Pretreatment of rats with phenobarbital or SKF 525-A protects against body weight loss and increase in relative lung wet weight induced by OSS-TMP. Light microsopic observation of lung tissue also indicates that these pretreatments abolish the abnormality of lung parenchyma. We postulate that pretreatment with phenobarbital or SKF 525-A induces the detoxification process(es) and inhibits the activation process(es) of OSS-TMP, respectively, resulting in a protective effect against OSS-TMP-induced toxicity. These findings further support the view that the lungs may be a target organ of delayed toxicity produced by OSS-TMP, and a metabolite(s) of OSS-TMP is involved in the manifestation of the toxicity.