Selective inhibition and induction of CYP activity discriminates between the isoforms responsible for the activation of butylated hydroxytoluene and naphthalene in mouse lung

Xenobiotica. 1997 Aug;27(8):853-64. doi: 10.1080/004982597240217.


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.

MeSH terms

  • Animals
  • Biotransformation
  • Body Weight
  • Butylated Hydroxytoluene / metabolism
  • Butylated Hydroxytoluene / pharmacokinetics*
  • Butylated Hydroxytoluene / toxicity
  • Cytochrome P-450 CYP2B1 / antagonists & inhibitors
  • Cytochrome P-450 CYP2B1 / metabolism
  • Cytochrome P-450 Enzyme Inhibitors
  • Cytochrome P-450 Enzyme System / biosynthesis*
  • Enzyme Inhibitors / pharmacology*
  • Female
  • Isoenzymes / antagonists & inhibitors
  • Isoenzymes / biosynthesis*
  • Lung / enzymology*
  • Lung / pathology
  • Lung Diseases / chemically induced
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Mice, Inbred DBA
  • Naphthalenes / metabolism
  • Naphthalenes / pharmacokinetics*
  • Organ Size
  • Organothiophosphates / pharmacology
  • Pyrazoles / pharmacology


  • Cytochrome P-450 Enzyme Inhibitors
  • Enzyme Inhibitors
  • Isoenzymes
  • Naphthalenes
  • Organothiophosphates
  • Pyrazoles
  • O,O,O-trimethyl phosphorothioate
  • Butylated Hydroxytoluene
  • naphthalene
  • pyrazole
  • Cytochrome P-450 Enzyme System
  • Cytochrome P-450 CYP2B1