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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