03- Semi-empirical and DFT analyses of the metabolism of pyrazinamide

Fazlul Huq and Zahed Hossain

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. Tel: +61 2 9351 9522 Fax: +61 2 9351 9520

E-mail : f.huq@fhs.usyd.edu.au.

Abstract: Tuberculosis is a global health problem of escalating proportions especially due to the prevalence of the acquired immunodeficiency syndrome (AIDS) has greatly increased the incidence of the disease over the first few years. A commonly used front-line anti-tuberculosis drug is pyrazinamide (PZA). PZA causes dose-dependent hepatotoxicity that is manifested by hepatocellular dysfunction. The exact of mechanism of action of PZA and that of its toxicity remain unclear. In vivo, PZA is metabolized in the liver to form the main metabolite pyrazinoic acid (PA) by enzymatic deamination. PA is oxidised by the action of xanthine oxidase (XO) to form 5-OH-PA which is the main excretory metabolite of PZA. PZA is also directly oxidised to form 5-OH-PZA by XO. A small amount of PU is produced by conjugation of PA with glycine. Molecular modelling analyses show that PZA and its metabolites may be subject to electrophilic attack at a number of sites including the two pyrazine ring nitrogens. The presence of some electron-deficient regions on the molecular surface indicates that PZA and its metabolites may also be subject to nucleophilic attack such as that by reduced form of glutathione and nucleobases in DNA. Similar but large HOMO-LUMO energy differences for PZA and all its metabolites mean that none can be excluded as being the cause for the toxicity of PZA although the rates of such adverse reactions are expected to below.

Key words: Pyrazinamide, tuberculosis, HIV, oxypurines, molecular modelling

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