International Journal of Pure and Applied Chemistry (IJPAC)

 

4. A Molecular modelling analysis of caffeine and its metabolites

Fazlul Huq

School of Biomedical Sciences, Faculty of Health Sciences, The University of Sydney

E-mail : f.huq@fhs.usyd.edu.au.

 

Abstract:

Caffeine is a widely consumed alkaloid that is present in coffee, tea, coca products and cola drinks. It produces increased alertness, decreased sleep, insomnia, and increased ability to work out cognitive problems. At low doses it produces an increased sense of well-being and mental capacity. With larger doses the irritability may develop into what is commonly known as ‘coffee nerves’. Caffeine is a CNS stimulator and acts as antagonist on adenosine receptors throughout the body. It undergoes extensive oxidative metabolism in humans and other mammalian species, initially by N-demethylation (which takes place almost exclusively in the liver) to produce theobromine, paraxanthine and theophylline and subsequently to 1,7-dimethylurate, 1-methylxanthine, and 1-methylurate. All of these primary and secondary metabolites of caffeine are excreted in urine. N3 demethylation of caffeine reflects the activity of cytochrome P4501A2 (CYP1A2) enzyme which is responsible for the activation of numerous promutagens and procarcinogens such as aromatic amines and heterocyclic amines so that high intake of caffeine may indirectly stimulate the activation of such promutagens and carcinogens. Molecular modelling analyses show that caffeine and all its metabolites have large solvation energy values so that they can be excreted easily in the form of urine. Neither caffeine nor its metabolites has relatively small LUMO-HOMO energy difference indicating that none would be highly labile. The high kinetic stability and high clearance rate for caffeine and all its metabolites may mean that none is likely to be extremely toxic. The metabolite AFMU has the smallest LUMO-HOMO energy difference (4.75 eV from DFT calculations) indicating that it will be somewhat more labile kinetically. The molecular surface of AFMU has some electron-deficient regions so that it can react with cellular nucleophiles such as glutathione causing its depletion. As the level of glutathione is reduced, the antioxidant status of the cell is compromised so that the toxicity of caffeine may be mediated via AFMU. Although, another metabolite TP abounds more in electron-deficient regions, its reaction with glutathione and other cellular nucleophiles is expected to be less significant because of its greater kinetic inertness.

 

Key words: Caffeine, metabolism, theobromine, paraxanthine, molecular modelling


 

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