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5- Metabolic activation of chloroform – a molecular
modelling analysis
Fazlul Huq
Discipline of Biomedical Science,
School
of Medical Sciences, Faculty of Medicine, The University of Sydney,
Australia.
Telephone: +61 2 9351 9522 Fax: +61 2 9351 9520
E-mail :
F.Huq@usyd.edu.au.
Abstract
Chloroform is a highly toxic halogenated hydrocarbon that is still
widely used as a solvent in industrial processes and formed as a
by-product during chlorination of water intended for human consumption
and paper bleaching. Molecular modelling analyses based on molecular
mechanics, semi-empirical (PM3) and DFT (at B3LYP/6-31G* level)
calculations show that chloform and its metabolites generally have
large LUMO-HOMO energy differences, indicating that they would be
kinetically inert, thus providing an explanation about their long
persistence in the environment. Concentration of negatively charged
regions on the molecular surfaces of chloroform and its metabolites
indicate that they may be subject to electrophilic attacks. However,
presence of some electron-deficient regions on the molecular surfaces
of phosgene, *CHCl2 and CCl3OH indicates that
they also react with cellular nucleophiles such as glutathione and
nucleobases in DNA, thus inducing cellular toxicity and DNA damage
respectively.
Key words:
Chloroform, phosgene, dichloromethane, toxicity, molecular modelling
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