|
04- Semi-empirical and DFT analyses of the metabolic
activation of ethylene glycol
Fazlul Huq and Deena Ababneh
School of Biomedical Sciences, Faculty of Health Sciences, The
University of Sydney
Correspondences author: Dr. Fazlul Huq,
School of Biomedical Sciences, Faculty of Health Sciences, 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@fhs.usyd.edu.au
Abstract:
Ethylene glycol is a highly toxic and widely used industrial chemical.
When ingested in the form of antifreeze or other automobile products,
ethylene glycol results in central nervous system depression,
cardiopulmonary compromise and renal dysfunction. The metabolic
degradation of ethylene glycol includes conversion to glycoladehyde,
glycolic acid, glyoxal, glyoxylic acid, oxalic acid, formic acid,
carbon dioxide and incorporation into glycine that occurs via a number
of intermediates. Preponderance of acids among the metabolites of
ethylene glycol explains why ethylene glycol can cause metabolic
acidosis. It has been established that the rate-determining step is
the step in which glycolic acid is converted to glyoxylic acid.
Molecular modelling analyses based on molecular mechanics,
semi-empirical (PM3) and DFT (at
B3LYP/6-31G* level)
calculations
show that glycolic acid has high thermodynamic stability and low
kinetic lability so that the reaction in which glycolic acid is
converted to glyoxylic acid is indeed rate-determining. The metabolite
glyoxal has the lowest LUMO-HOMO energy difference that makes it most
kinetically labile. The high kinetic lability and the presence of
electron-deficient region on the molecular surface may make glyoxal
the most toxic metabolite as it may induce cellular toxicity due to
depletion of reduced form of glutathione and cause DNA damage due to
oxidation of nucleobases in DNA.
Key words:
ethylene glycol, metabolic degradation, glycolaldehyde, glycolic acid,
glyoxal, oxalic acid
<<< |
