THEORETICAL-STUDY ON THE METABOLISM OF CAFFEINE BY CYTOCHROME-P-450 1A2 AND ITS INHIBITION

The primary metabolism of caffeine (1,3,7-trimethylxanthine) is catalyzed by the isozyme P-450 1A2 which has toxicological relevance because it is involved in the activation of some chemicals to carcinogenic compounds. A theoretical model for the demethylation of caffeine is proposed by means of the study of the molecular electrostatic potential (MEP) distributions of caffeine and other xanthine derivatives that are inhibitors of this metabolic process. Negative zones of these distributions show a common triangular pattern in the xanthine plane. The model proposes that the alignment of the caffeine molecule in the active site is determined by these negative MEP zones. An interesting finding was that all the methyl groups to be removed have at least a MEP minimum at a distance of approximately 3 Angstrom. This feature would explain the preference for the N-3 demethylation leading to paraxanthine (1,7-dimethylxanthine) because only this methyl group is placed at a distance of 3 Angstrom from the deepest MEP minimum. Another experimental observation consistent with the proposed model is the inhibition of caffeine demethylation by several 8-methylxanthines. Among them, 1,3,8-trimethylxanthine, furafylline (1,8-dimethyl-3-(2-furfuryl)xanthine) and 1,8-dimethyl-3-phenylxanthine were considered in the present study. The inhibition is explained by the fact that all these compounds have a methyl on C-8 placed at a distance of 3 Angstrom from the deepest MEP minimum.