02- Molecular modelling analysis of the metabolism of benzene

Fazlul Huq

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: Benzene is a ubiquitous environmental pollutant and an industrial chemical that is used in the manufacture of a wide variety of consumer goods such as plastic containers, toys, radios, sporting goods, furniture, tyres, adhesives, textiles, dyes, drugs, pesticides, lubricants, solvents and cleaning agents. It is also a constituent of leaded petrol. Epidemiological studies show that the occupational exposure to benzene is linked to the incidence of bone marrow toxicity and a variety of leukemias in humans. Molecular modelling analyses based on molecular mechanics, semi-empirical and DFT calculations give support to the idea that the toxicity of benzene is mediated through metabolic activation. In particular, the analyses show that the toxic metabolites 1,2-benzoquinone, 1,4-benzoquinone and trans,trans-muconaldehyde have smallest LUMO-HOMO differences so that they would be most reactive kinetically. The high kinetic lability and the presence of electron-deficient regions on the molecular surface mean that the metabolites may react readily with glutathione and nucleobases in DNA, thus causing oxidative stress due to glutathione depletion and DNA damage due to oxidation of nucleobases.

Key words: Benzene, glutathione, toxicity, molecular modelling

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