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 A. This feature would explain the preference for the N3 demethylation leading to paraxanthine (1,7-dimethylxanthine) because only this methyl group is placed at a distance of 3 A 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 C8 placed at a distance of 3 A from the deepest MEP minimum.

[1]  B K Tang,et al.  Biotransformation of caffeine by microsomes from human liver. Kinetics and inhibition studies. , 1987, Biochemical pharmacology.

[2]  P. Beaune,et al.  Human drug metabolism in vitro. , 1988, Pharmacology & therapeutics.

[3]  E I Canela,et al.  Theoretical study of the protonation and tautomerization of adenosine, formycin, and their 2-NH2 and 2-F derivatives: functional implications in the mechanism of reaction of adenosine deaminase. , 1989, Molecular pharmacology.

[4]  B. Tang,et al.  Caffeine as a metabolic probe: Exploration of the enzyme‐inducing effect of cigarette smoking , 1991, Clinical pharmacology and therapeutics.

[5]  Peter Politzer,et al.  Correlations between molecular electrostatic potentials and some experimentally-based indices of reactivity , 1992 .

[6]  T. Shimada,et al.  Human liver microsomal cytochrome P-450 enzymes involved in the bioactivation of procarcinogens detected by umu gene response in Salmonella typhimurium TA 1535/pSK1002. , 1989, Cancer research.

[7]  F. Gonzalez,et al.  Human cytochromes P450: problems and prospects. , 1992, Trends in pharmacological sciences.

[8]  A. Guillouzo,et al.  Evidence for the involvement of several cytochromes P-450 in the first steps of caffeine metabolism by human liver microsomes. , 1991, Drug metabolism and disposition: the biological fate of chemicals.

[9]  J. Collins,et al.  Theoretical study of the product specificity in the hydroxylation of camphor, norcamphor, 5,5-difluorocamphor, and pericyclocamphanone by cytochrome P-450cam. , 1988, The Journal of biological chemistry.

[10]  Ferran Sanz,et al.  MEPSIM: A computational package for analysis and comparison of molecular electrostatic potentials , 1993, J. Comput. Aided Mol. Des..

[11]  M. Arnaud,et al.  Caffeine: A Model Compound for Measuring Liver Function , 1984, Hepatology.

[12]  Jeremy G. Vinter,et al.  Electrostatics and computational modelling Editorial overview , 1991, J. Comput. Aided Mol. Des..

[13]  U. Fuhr,et al.  Biotransformation of caffeine and theophylline in mammalian cell lines genetically engineered for expression of single cytochrome P450 isoforms. , 1992, Biochemical pharmacology.

[14]  R. Osman,et al.  On the structural and mechanistic basis of function, classification, and ligand design for 5-HT receptors. , 1990, Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology.

[15]  D. Grant,et al.  Biotransformation of caffeine, paraxanthine, theophylline, and theobromine by polycyclic aromatic hydrocarbon-inducible cytochrome(s) P-450 in human liver microsomes. , 1987, Drug metabolism and disposition: the biological fate of chemicals.

[16]  B Testa,et al.  Molecular electrostatic potential of orthopramides: implications for their interaction with the D-2 dopamine receptor. , 1986, Journal of medicinal chemistry.

[17]  B. Luke,et al.  Theoretical Studies of Cytochrome P-450 , 1986 .

[18]  B. Luke,et al.  Theoretical studies of cytochrome P-450. Characterization of stable and transient active states, reaction mechanisms and substrate-enzyme interactions. , 1986, Enzyme.

[19]  Ferran Sanz,et al.  Automatic determination of MEP patterns of molecules and its application to caffeine metabolism inhibitors , 1988 .

[20]  T. Shimada,et al.  Oxidation of toxic and carcinogenic chemicals by human cytochrome P-450 enzymes. , 1991, Chemical research in toxicology.

[21]  R. Osman,et al.  A molecular model for activation of a 5-hydroxytryptamine receptor. , 1987, Molecular pharmacology.

[22]  David F. V. Lewis,et al.  The sequence homologies of cytochromes P-450 and active-site geometries , 1992, J. Comput. Aided Mol. Des..

[23]  T. Poulos.  Reversing enzyme specificity , 1989, Nature.