Inhibition and induction of cytochrome P450 isoenzymes in rat lung.
The O-dealkylation of pentoxyresorufin, a substrate for P450 2B1, was decreased in lung microsomes from rats dosed with O,O,S-trimethylphosphorodithioate, O,O,O-trimethylphosphorothioate, bromophos, fenitrothion, p-xylene and 2,4-dichloro-(6-phenylphonoxy)ethylamine. This activity was decreased by antibodies to P450 2B1 but unaffected by antibodies to P450 1A1 or 4B1. This reduction reflected both inactivation and destruction of P450 2B1; destruction of this protein was particularly marked after bromophos and fenitrothion. Pyrazole was the only compound in this study to induce the O-dealkylation of pentoxyresorufin. None of these compounds altered the rate of ethoxyresorufin O-dealkylation, an indicator of P450 1A1 activity, but this activity was induced greatly by both Aroclor and beta-naphthoflavone, p-Xylene was the only compound to decrease P450 4B1 activity, as determined by the N-hydroxylation of 2-aminofluorene. In the liver, bromophos, fenitrothion, p-xylene and 2,4-dichloro-(6-phenylphonoxy)ethylamine all had marked effects on the O-dealkylation of ethoxyresorufin and pentoxyresorufin but, at the dose used, O,O,O-trimethylphosphorothioate and O,O,S-trimethylphosphorodithioate had minimal effects in this tissue. Thus, both O,O,O-trimethylphosphorothioate and O,O,S-trimethylphosphorodithioate are exquisitely selective inhibitors of pulmonary P450 2B1 activity. Their use, together with pyrazole, will facilitate future studies of the pulmonary activation of toxins by P450 2B1.
Verschoyle
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RD
MRC Toxicology Unit, Carshalton, Surrey, England.
Dinsdale
D
D
Wolf
C R
CR
D000818:Animals; D015153:Blotting, Western; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis*; D004790:Enzyme Induction; D005260:Female; D005449:Fluorenes / Q000378:metabolism; D006900:Hydroxylation; D007527:Isoenzymes / Q000037:antagonists & inhibitors* / Q000096:biosynthesis*; D008168:Lung / Q000187:drug effects / Q000201:enzymology*; D008861:Microsomes / Q000187:drug effects / Q000201:enzymology; D063086:Organothiophosphates / Q000494:pharmacology; D010078:Oxazines / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar
D065607:Cytochrome P-450 Enzyme Inhibitors; D005449:Fluorenes; D007527:Isoenzymes; D063086:Organothiophosphates; D010078:Oxazines; C023890:O,O,O-trimethyl phosphorothioate; C019123:O,O,S-trimethyl phosphorothioate; C012177:2-aminofluorene; C007649:ethoxyresorufin; C057754:benzyloxyresorufin; C044943:pentoxyresorufin; D003577:Cytochrome P-450 Enzyme System