6- Metabolic activation of paracetamol – a molecular modelling analysis

Fazlul Huq

Discipline of Biomedical Science, School of Medical Sciences,Faculty of Medicine, The University of Sydney, Australia.Telephone: +61 2 9351 9522 Fax: +61 2 9351 9520 E-mail :F.Huq@usyd.edu.au.

Abstract

Paracetamol is probably the most versatile and widely used analgesic and antipyretic drug all over the world and is also one of the commonest means of committing suicide. Molecular modelling analyses based on molecular mechanics, semi-empirical (PM3) and DFT (at B3LYP/6-31G* level) show that among paracetamol and its metabolites, NAPQI has the highest kinetic lability and lower solubility in water, and abounds most in electron-deficient blue regions so that it can react readily with glutathione and nucleobases in DNA. The oxidative stress due to glutathione depletion would induce cellular toxicity and oxidation of nucleobases in DNA would cause DNA damage.

Key words: Paracetamol, paracetamol sulfate, glutathione, necrosis, molecular modelling

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