Molecular Modelling Analysis of the Metabolism of Naphthalene
Naphthalene is a bicyclic aromatic hydrocarbon widely used as an intermediate in chemical and plastics industry and in the manufacture of insecticides and fungicides. It is metabolized by microsomal enzymes to naphthols and dihydrodiols via the formation of an epoxide which has a very short half-life. Reactive metabolites of naphthalene can deplete glutathione and in the absence of sufficient glutathione, get covalently bound to tissue macromolecules. In this study, molecular modelling analyses based on molecular mechanics, semi-empirical and DFT calculations have been carried out to provide information on the relative stability of naphthalene and its metabolites, deemed to be useful in the understanding of naphthalene induced toxicity. The analyses show that although naphthalene has a low thermodynamic stability, the larger LUMO-HOMO energy difference makes it less labile kinetically and hence less toxic than its more labile metabolites. Although naphthalene-1,2-epoxide has the lowest thermodynamic stability, the larger LUMO-HOMO energy difference makes the epoxide also labile. Much lower LUMO-HOMO energy differences make the naphthoquinones more reactive and hence more toxic.
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