05- Metabolic activation  of naphthalene –a molecular modelling analysis

Fazlul Huq

School of Biomedical Sciences, Faculty of Health Sciences, the University of Sdyney

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. Tel.: +61 2 9351 9522 Fax: +61 2 9351 9520 E-mail : f.huq@fhs.usyd.edu.au

Abstract: 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.

Molecular modelling analyses based on molecular mechanics, semi-empirical and DFT calculations show that although naphthalene has a low thermodynamic stability but large HOMO-LUMO energy difference that makes it less kinetically labile. In contrast, naphthalene-1,2-epoxide has low thermodynamic stability but large HOMO-LUMO energy difference making it also less labile kinetically whereas naphthoquinones have much lower HOMO-LUMO energy differences that would make them more reactive kinetically. The high kinetic and the presence of electron-deficient regions on the molecular surface mean that napthoquinones can react readily with glutathione and nucleobases in DNA. Reaction with glutathione induces cellular toxicity associated with glutathione depletion whereas oxidation of nucleobases would cause DNA damage.

Key words: Naphthalene, glutathione, toxicity, molecular modelling

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