Oxidation of caffeine to theobromine and theophylline is catalyzed primarily by flavin-containing monooxygenase in liver microsomes

Biochem Biophys Res Commun. 1997 Jun 27;235(3):685-8. doi: 10.1006/bbrc.1997.6866.


Upon N-demethylation of caffeine (CA) by rat and human liver microsomes, theobromine (TB), paraxanthine (PX), and theophylline (TP) are produced. The optimal pHs for the formation of TB, PX, and TP from CA by rat liver microsomes are 7.4 (most), 8.2 (minor) and 8.6 (moderate). At pH 7.4, PX is the primary metabolite formed and makes up 48% of the CA metabolites generated. In the presence of SKF525A, an inhibitor of P450 (CYP), the rates of TB, PX and TP production are inhibited by 32%, 68% and 42%, respectively. Alternatively, in the presence of methimazole, an inhibitor of flavin-containing monooxygenase (FMO), the rates of TB, PX and TP production are inhibited by 66%, 48% and 73%, respectively. In the presence of both SKF525A and methimazole, they are inhibited by 95%, 84% and 94%, respectively. With human liver microsomes, the CA is metabolized faster but is inhibited more extensively either by SKF525A (PX production) or by methimazole (TB production). Alternatively, when CA is metabolized at pH 8.6, the optimal pH of FMO catalyzed reaction, the rates of TB and TP formation are increased but the rate of PX production is decreased. Furthermore, at pH 8.6 and in the presence of methimazole, the rates of TB and TP formation are decreased by 82% and 95%, respectively. These results indicate that the FMO is responsible primarily for productions of TB and TP and the CYP for PX.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Biotransformation
  • Caffeine / pharmacokinetics*
  • Humans
  • Hydrogen-Ion Concentration
  • Kinetics
  • Male
  • Methimazole / pharmacology
  • Microsomes, Liver / drug effects
  • Microsomes, Liver / enzymology*
  • Oxidation-Reduction
  • Oxygenases / metabolism*
  • Proadifen / pharmacology
  • Rats
  • Rats, Sprague-Dawley
  • Species Specificity
  • Theobromine / pharmacokinetics*
  • Theophylline / pharmacokinetics*


  • Caffeine
  • Methimazole
  • Proadifen
  • Theophylline
  • Oxygenases
  • dimethylaniline monooxygenase (N-oxide forming)
  • Theobromine