Protection against chemical-induced lung injury by inhibition of pulmonary cytochrome P-450.
Protection afforded by trialkyl phosphorothionates against the lung injury caused by trialkyl phosphorothiolates probably results from the inhibition by the P = S moiety of the thionates, of one or more pulmonary cytochrome P-450 isozymes. The aromatic hydrocarbons p-xylene and pseudocumene also protect against this injury and inhibit some P-450 isozymes, but by a different mechanism. OOS-Trimethylphosphorothionate and p-xylene were compared as protective agents against the effect of OOS-trimethylphosphorothiolate and two other lung toxins ipomeanol and 1-nitronaphthalene that are known to be activated by cytochrome P-450. The effects of these protective compounds, in vivo, on pulmonary cytochrome P-450 activity were also determined. Both compounds inhibited pentoxyresorufin O-deethylase activity, but not ethoxyresorufin O-deethylase. The phosphorothionate was most effective against lung injury caused by the phosphorothiolates and 1-nitronaphthalene, whereas p-xylene was much more effective against ipomeanol. beta-Naphthoflavone, which induces pulmonary ethoxyresorufin O-deethylase activity, did not protect against phosphorothiolate or 1-nitronaphthalene injury, and it was only marginally effective in decreasing the toxicity of ipomeanol.
Verschoyle
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RD
MRC Toxicology Unit, Medical Research Council Laboratories, Carshalton Surrey, UK.
Dinsdale
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D
D000284:Administration, Oral; D000818:Animals; D002273:Carcinogens / Q000633:toxicity*; D019363:Cytochrome P-450 CYP1A1; D019362:Cytochrome P-450 CYP2B1; D003577:Cytochrome P-450 Enzyme System / Q000502:physiology*; D005260:Female; D008171:Lung Diseases / Q000139:chemically induced / Q000188:drug therapy* / Q000201:enzymology; D009281:Naphthalenes / Q000633:toxicity*; D063086:Organothiophosphates / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use* / Q000633:toxicity*; D009946:Organothiophosphorus Compounds / Q000627:therapeutic use* / Q000633:toxicity*; D010088:Oxidoreductases / Q000502:physiology; D051381:Rats; D013729:Terpenes / Q000633:toxicity*; D014118:Toxins, Biological / Q000633:toxicity*; D014992:Xylenes / Q000494:pharmacology / Q000627:therapeutic use*
D002273:Carcinogens; D009281:Naphthalenes; D063086:Organothiophosphates; D009946:Organothiophosphorus Compounds; D013729:Terpenes; D014118:Toxins, Biological; D014992:Xylenes; C019123:O,O,S-trimethyl phosphorothioate; C033125:O,S,S-trimethyl phosphorodithioate; C065349:O,O,S-trimethylphosphorodithionate; C031286:4-xylene; D003577:Cytochrome P-450 Enzyme System; C016614:1-nitronaphthalene; D010088:Oxidoreductases; D019363:Cytochrome P-450 CYP1A1; D019362:Cytochrome P-450 CYP2B1; C001470:4-ipomeanol