title: Selective inhibition and induction of CYP activity discriminates between the isoforms responsible for the activation of butylated hydroxytoluene and naphthalene in mouse lung.
abstract: 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.
authors.affiliation: MRC Toxicology Unit, Leicester, UK.
authors.forename: R D
authors.initials: RD
authors.lastname: Verschoyle
authors.forename: J
authors.initials: J
authors.lastname: Martin
authors.forename: D
authors.initials: D
authors.lastname: Dinsdale
mesh_terms: 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
chemical_list: 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