Isoform-selective mechanism-based inhibition of human cytochrome P450 1A2 by furafylline

Chem Res Toxicol. 1993 Sep-Oct;6(5):649-56. doi: 10.1021/tx00035a009.


Biotransformation reactions catalyzed by human cytochrome P450 1A2 (P450 1A2) appear to play a significant role in both the metabolic clearance of drugs and the activation of environmental contaminants and drugs to toxic or carcinogenic species. Furafylline is a potent and selective inhibitor of P450 1A2 activity in human liver microsomes [Sesardic, D., Boobis, A., Murray, B., Murray, S., Segura, J., De La Torre, R., and Davies, D. (1990) Br. J. Clin. Pharmacol. 29, 651-663] which may be of great utility in defining the role of P450 1A2 in metabolic processes. We have investigated the hypothesis that furafylline is a mechanism-based inhibitor of P450 1A2. Key findings consistent with this hypothesis are the following: (1) Furafylline causes a time- and cofactor-dependent loss of P450 1A2 activity which does not return upon dialysis. (2) The loss of activity is associated with a reduction of P450 spectral content which is in turn proportional in amount to P450 1A2-associated catalytic activity in uninhibited microsomes from 7 individual livers. (3) The inactivation of P450 1A2 is characterized by a Ki of 23 microM, a kinact of 0.87 min-1 and a furafylline depletion-based partition ratio of approximately 3-6 metabolic events per inactivating event. (4) The processing of the C-8 methyl group of furaylline is involved in inactivation as demonstrated by the observation of a deuterium isotope effect of approximately 2.0 on kinact and no effect on Ki when the C-8 methyl group protons of furafylline are replaced with deuterium atoms.(ABSTRACT TRUNCATED AT 250 WORDS)

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Biotransformation
  • Cytochrome P-450 CYP1A2
  • Cytochrome P-450 Enzyme Inhibitors*
  • Dialysis
  • Humans
  • In Vitro Techniques
  • Isoenzymes / antagonists & inhibitors*
  • Kinetics
  • Microsomes, Liver / drug effects
  • Microsomes, Liver / enzymology
  • NADP / metabolism
  • Oxidoreductases / antagonists & inhibitors*
  • Theophylline / analogs & derivatives*
  • Theophylline / chemical synthesis
  • Theophylline / pharmacology


  • Cytochrome P-450 Enzyme Inhibitors
  • Isoenzymes
  • NADP
  • Theophylline
  • furafylline
  • Oxidoreductases
  • Cytochrome P-450 CYP1A2