Molecular Modelling Analysis of the Metabolism of Toluene
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. Recent investigations have shown that toluene may induce reproductive dysfunctions and cancer. However, little is known about the molecular mechanisms by which toluene elicits its toxic effects on male reproductive organs and carcinogenicity. Following exposure in humans, toluene is readily transformed into several metabolites including benzyl alcohol, ortho-, meta- and para-cresols. The main metabolic pathway involves its oxidation to benzyl alcohol which is further oxidised to benzoic acid via benzaldehyde and excreted in the urine as hippuric acid. Ortho-, meta- and para-cresols are formed as minor metabolites through the formation of epoxides although there is evidence for direct hydroxylation of aromatic ring. Ortho-cresol is further hydroxylated to form MHQ which on oxidation produces MBQ. Molecular modelling analyses based on molecular mechanics, semi-empirical and DFT calculations show that the most toxic metabolite of toluene namely MBQ has the smallest LUMO-HOMO energy difference and hence it will be most reactive kinetically. The presence of electron-rich and electron-deficient sites indicates that the metabolite may undergo both electrophilic and nucleophilic attacks, the latter providing an explanation as to why it can cause oxidative damage to DNA.
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