Theophylline metabolism by human, rabbit and rat liver microsomes and by purified forms of cytochrome P450

J Pharm Pharmacol. 1988 Jun;40(6):388-91. doi: 10.1111/j.2042-7158.1988.tb06301.x.


The capacity of human, rabbit and rat liver microsomes and purified isozymes of cytochrome P450 to metabolize theophylline has been assessed. In all three species the 8-hydroxylation of theophylline to 1,3-dimethyluric acid (1,3-DMU) was the major pathway. In human, control rabbit and rat liver microsomes this metabolite accounted for 59, 77 and 94%, respectively, of the total metabolites formed. In both human and control rabbit liver microsomes the N-demethylation of theophylline to 1-methylxanthine (1-MX) accounted for 20% of the total metabolites formed. N-demethylation of theophylline to 3-methylxanthine (3-MX) accounted for 21% of theophylline metabolism in human microsomes but was a minor pathway in control rabbit and rat microsomes. Acetone and phenobarbitone pretreatment markedly increased the formation of 1,3-DMU by rabbit liver microsomes. Rifampicin and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) administration caused a slight but significant increase in this pathway. In general the N-demethylation pathways in rabbit liver microsomes were refractory to induction. In the rat, the metabolism of theophylline to 1-MX, 3-MX and 1,3-DMU were all significantly increased in Aroclor 1254, dexamethasone, phenobarbitone and 3-methylcholanthrene-treated microsomes. In reconstitution experiments the polycyclic hydrocarbon inducible rabbit cytochrome P450 Forms 4 and 6 and the constitutive Form 3b all metabolized theophylline to its three metabolites. In human liver microsomes from four subjects anti-rabbit cytochrome P450 Form 4 IgG inhibited the metabolism of theophylline to 1-MX, 3-MX and 1,3-DMU by approximately 30%. These data indicate that theophylline is metabolized by multiple forms of cytochrome P450 in human, rabbit and rat liver microsomes.

MeSH terms

  • Animals
  • Biotransformation
  • Cytochrome P-450 Enzyme System / metabolism*
  • Female
  • Humans
  • In Vitro Techniques
  • Male
  • Microsomes, Liver / enzymology
  • Microsomes, Liver / metabolism*
  • Rabbits
  • Rats
  • Rats, Inbred Strains
  • Species Specificity
  • Theophylline / metabolism*
  • Uric Acid / analogs & derivatives
  • Uric Acid / metabolism
  • Xanthines / metabolism


  • Xanthines
  • Uric Acid
  • 1-methylxanthine
  • Cytochrome P-450 Enzyme System
  • Theophylline
  • 1,3-dimethyluric acid
  • 3-methylxanthine