Cell-specific loss of cytochrome P450 2B1 in rat lung following treatment with pneumotoxic and non-pneumotoxic trialkylphosphorothioates.
This study was designed to test the hypothesis that the reduction in cytochrome P450 (CYP) 2B1 content and activity of rat lung microsomes, following dosing with pneumotoxic trimethylphosphorothioates, results from damage to specific cell types. Of the lung cells exhibiting immunolabelling for CYP2B1, only type I cells showed signs of susceptibility to the pneumotoxins O,O.S-trimethylphosphorothioate and O,S,S-trimethylphosphorodithioate. While most type I cells became necrotic, type II and Clara cells showed no signs of injury, despite their gradual loss of CYP2B1, as detected by immunogold labelling. This loss of labelling was accompanied by a 75% reduction in the immunoreactive CYP2B1 content and an 85% reduction in pentoxyresorufin O-dealkylase activity in lung microsomes. In contrast, the non-pneumotoxic analogue O,O,S-trimethylphosphorodithioate, differing from O,O,S-trimethylphosphorothioate by only the presence of a P = S rather than a P = O moiety, caused an even more rapid fall in pulmonary pentoxyresorufin O-dealkylase activity, but only a slight reduction in the microsomal content of CYP2B1. The recovery of this activity began within 12 hr of dosing. O,O,S-Trimethylphosphorodithioate, which acts as a suicidal inhibitor of pulmonary CYP2B1, did not cause any detectable lung injury or increase in cell division. These results are consistent with the initial reduction in both enzyme content and activity caused by the P = O - containing pneumotoxins resulting, almost entirely, from death of type I cells. Subsequent reductions that occur long after clearance of the toxin may be exacerbated by the onset of mitosis in Clara and type II cells.
MRC Toxicology Unit, PO Box 138, Lancaster Road, LE1 9HN, Leicester, UK. dd5@le.ac.uk
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Dinsdale
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Verschoyle
D000818:Animals; D002800:Cholinesterase Inhibitors / Q000494:pharmacology; D019362:Cytochrome P-450 CYP2B1 / Q000378:metabolism*; D007150:Immunohistochemistry; D008168:Lung / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D008297:Male; D063086:Organothiophosphates / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D013347:Subcellular Fractions / Q000378:metabolism
D002800:Cholinesterase Inhibitors; D063086:Organothiophosphates; C019123:O,O,S-trimethyl phosphorothioate; C033125:O,S,S-trimethyl phosphorodithioate; C065349:O,O,S-trimethylphosphorodithionate; D019362:Cytochrome P-450 CYP2B1