3- A molecular modelling analysis of the toxicity of Aflatoxin B₁ and its modulation by Chlorophyllin

Fazlul Huq and Nurhanan Murni Yunos

 Discipline of Biomedical Science, School of Medical Sciences, Faculty of Medicine,

Cumberland Campus, C42, The University of Sydney, PO Box 170 Lidcombe, NSW 1825, Australia. Phone: 061 2 9351 9522; Fax: 061 2 9351 9520
Email: F.Huq@fhs.usyd.edu.au

Aflatoxins, particularly aflatoxin B₁ (AFB1), are potent hepatocarcinogens produced by fungi. Molecular modelling analyses based on molecular mechanics, semi-empirical (PM3) and DFT (at B3LYP/6-31G* level) calculations show that both AFB1 and its major metabolite AFB1-8,9-oxide have moderately large LUMO-HOMO energy differences so that they would be neither highly labile nor extremely inert kinetically. The molecular surfaces of both AFB1 and AFB1-8,9-oxide are found to abound in electron-deficient regions so that they can react with cellular nucleophiles such as glutathione and nucleobases in DNA, thus causing depletion of glutathione and oxidation of nucleobases. The former would induce cellular toxicity due to oxidative stress and the latter would cause DNA damage. However, because of somewhat kinetic inertness of AFB1 and AFB1-8,9-oxide, the rates of such adverse reactions are expected to be low unless speeded up enzymatically. The results of the study also indicate that the protective role played by CLP may be mediated by electrostatic interaction between AFB1 and CLP, and that the covalent binding between AFB1-8,9-oxide and guanine causing DNA damage may be preceded by electrostatic attraction.

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