Cytochrome P450 2B isoenzymes are responsible for the pulmonary bioactivation and toxicity of butylated hydroxytoluene, O,O,S-trimethylphosphorothioate and methylcyclopentadienyl manganese tricarbonyl.
O,O,S-Trimethylphosphorothioate and methylcyclopentadienyl manganese tricarbonyl damage the type I pneumocytes of the alveolar epithelium in rats. Butylated hydroxytoluene causes similar damage in mice. The toxicity of these compounds is dependent on their bioactivation by the cytochrome P-450 (CYP) system. A range of compounds, that modifies the activity of specific CYP isoenzymes, has been used to establish those particular isoenzymes involved in bioactivation. Pulmonary toxicity was assessed by measurement of lung weight and changes in the activity of gamma-glutamyltranspeptidase and alkaline phosphatase in bronchoalveolar lavage fluid. O,O,S-Trimethylphosphorodithioate, bromophos, p-xylene and 2,4-dichloro-(6-phenyl-phenoxy)ethylamine all inhibited the dealkylation of pentoxyresorufin, an indicator of CYP2B1 activity, and also prevented pulmonary toxicity. There was a significant negative correlation between the level of pulmonary pentoxyresorufin dealkylation after pretreatment with O,O,S-trimethylphosphorodithioate and the severity of lung injury. This pretreatment also reduced the toxicity of butylated hydroxytoluene by a factor of 20 and methylcyclopentadienyl manganese tricarbonyl by a factor of 10. Modification of the activity of CYP1A1, CYP2E1 and CYP4B1 did not alter the toxicity of these compounds. These results indicate that pulmonary CYP2B1 is responsible for the bioactivation and toxicity of O,O,S-trimethylphosphorothioate and methylcyclopentadienyl manganese tricarbonyl in rats and the orthologous 2B isoenzyme in mice activates butylated hydroxytoluene.
Verschoyle
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MRC Toxicology Unit, MRC Laboratories, Carshalton, Surrey, United Kingdom.
Wolf
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CR
Dinsdale
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D000818:Animals; D001711:Biotransformation; D002084:Butylated Hydroxytoluene / Q000493:pharmacokinetics* / Q000633:toxicity; D003577:Cytochrome P-450 Enzyme System / Q000502:physiology*; D005260:Female; D005978:Glutathione / Q000502:physiology; D007527:Isoenzymes / Q000502:physiology*; D008168:Lung / Q000187:drug effects*; D009942:Organometallic Compounds / Q000493:pharmacokinetics* / Q000633:toxicity; D063086:Organothiophosphates / Q000493:pharmacokinetics* / Q000633:toxicity; D051381:Rats; D017208:Rats, Wistar
D007527:Isoenzymes; D009942:Organometallic Compounds; D063086:Organothiophosphates; C009907:2-methylcyclopentadienyl manganese tricarbonyl; C019123:O,O,S-trimethyl phosphorothioate; D002084:Butylated Hydroxytoluene; D003577:Cytochrome P-450 Enzyme System; D005978:Glutathione