Selective inhibition and induction of CYP activity discriminates between the isoforms responsible for the activation of butylated hydroxytoluene and naphthalene in mouse lung.
1. Selective induction and inhibition experiments have been used to identify the cytochrome P450 (CYP) isoforms responsible for butylated hydroxytoluene (BHT) bioactivation in mouse lung. 2. Pre-treatment of BALB/c mice with O,O,O-trimethylphosphorothioate (OOOMeP(S)), which prevented all the signs of toxicity observed following BHT treatment, inhibited the pulmonary activity of pentoxyresorufin O-dealkylase (PROD) and coumarin hydroxylase but not 4-nitrophenol hydroxylase. 3. Pulmonary coumarin hydroxylase activity was greater in DBA than in BALB/c mice but the severity of BHT-induced lung injury was similar. 4. Pre-treatment with pyrazole, which exacerbated BHT-induced lung injury, did not affect pulmonary coumarin hydroxylase or 4-nitrophenol hydroxylase activity but increased that of PROD. 5. Pre-treatment with OOOMeP(S) prevented the lethargy and weight-loss associated with naphthalene poisoning but not the pulmonary injury. Pre-treatment with pyrazole did not exacerbate naphthalene-induced injury. 6. Members of both CYP2F and 2B sub-families have been shown to exhibit PROD activity and 2F2 activates naphthalene in mouse lung. The current studies, however, indicate that 2F2 is unlikely to be a significant component of PROD activity in mouse lung. 2F2, like coumarin hydroxylase (2A5) and 4-nitrophenol hydroxylase (2E1), is not responsible for the pulmonary activation of BHT, which is largely attributable to an isoform of 2B, probably 2B10.
Verschoyle
R D
RD
MRC Toxicology Unit, Leicester, UK.
Martin
J
J
Dinsdale
D
D
D000818:Animals; D001711:Biotransformation; D001835:Body Weight; D002084:Butylated Hydroxytoluene / Q000378:metabolism / Q000493:pharmacokinetics* / Q000633:toxicity; D019362:Cytochrome P-450 CYP2B1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005260:Female; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D008168:Lung / Q000201:enzymology* / Q000473:pathology; D008171:Lung Diseases / Q000139:chemically induced; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D009281:Naphthalenes / Q000378:metabolism / Q000493:pharmacokinetics*; D009929:Organ Size; D063086:Organothiophosphates / Q000494:pharmacology; D011720:Pyrazoles / Q000494:pharmacology
D065607:Cytochrome P-450 Enzyme Inhibitors; D004791:Enzyme Inhibitors; D007527:Isoenzymes; D009281:Naphthalenes; D063086:Organothiophosphates; D011720:Pyrazoles; C023890:O,O,O-trimethyl phosphorothioate; D002084:Butylated Hydroxytoluene; C031721:naphthalene; C031280:pyrazole; D003577:Cytochrome P-450 Enzyme System; D019362:Cytochrome P-450 CYP2B1