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Molecular modelling analysis of the metabolism of mifepristone
Fazlul
Huq
Discipline of Biomedical Science, Faculty of
Medicine, The University of Sydney
Address reprint requests and correspondences to:
Dr. Fazlul
Huq, Discipline of Biomedical Science, Faculty of Medicine, C42, The
University of Sydney,
PO Box 170,
Lidcombe, NSW 1825, Australia.
Telephone: +61
2 9351 9522 Fax: +61 2 9351 9520
E-mail :
F.Huq@usyd.edu.au.
Key
words:
Mifepristone, RU486, steroid,
abortion,
molecular
modelling
Abstract
RU486 is a synthetic 19-nor-steroid that binds strongly to
progesterone as well as glucocorticoid receptors, thus acting as an
antagonist to progestational and glucocorticoid functions. Currently
RU486 is used as an abortifacient in France, UK, Sweden and China. The
side effects of RU486 include abdominal pain, cramping, nausea,
vomiting, bleeding, and delay in onset of the next menstrual cycle.
Molecular modelling analyses based on molecular mechanics,
semi-empirical and DFT (at
B3LYP/6-31G* level)
calculations
show that
RU486 and its metabolites are all fairly inert kinetically except FMFP
which is much more labile. The presence of some electron-deficient
regions on the molecular surfaces of RU486 and all its metabolites
indicates that none of the compounds may be totally immune to
nucleophilic attack. However, the rates of such adverse reactions are
expected to be low for RU486 and all its metabolites except for the
kinetically labile metabolite FMFP so that FMFP could induce cellular
toxicity associated with glutathione depletion and DNA damage from
oxidation of nucleobases.
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