14- Metabolic activation of toluene – 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

Toluene has been widely used as an organic solvent, ingredient of thinners, as a coating in the leather industry and in the synthesis of a number of chemicals. It is a common cause of neurotoxicity in people that intentionally and repetitively breather high concentrations of toluene over a long period of time. Molecular modelling analyses based on molecular mechanics, semi-empirical (PM3) and DFT (at B3LYP/6-31G* level) calculations show that toluene and its major metabolites have LUMO-HOMO energy differences ranging from 3.8 to 6.6 eV from DFT calculations, indicating that the compounds would vary significantly in their kinetic lability. The presence of electron-deficient sites on the molecular surface of its most kinetically labile metabolite MBQ indicates that the compound may be subject to nucleophilic attack by cellular nucleophiles such as glutathione and nucleobases in DNA. Reaction with glutathione would induce cellular toxicity due to glutathione depletion and the oxidation of nucleobases would cause DNA damage. Another two other metabolites hippuric acid and toluene-2,3-epoxide may also be subject to nucleophilic attack by glutathione and nucleobases in DNA. However, as the compounds are likely to be much less reactive kinetically than MBQ, the effects of such adverse reactions are expected to be less significant for them.

Key words: Toluene, glutathione, toxicity, molecular modelling

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