Molecular Modelling Analysis of the Metablism of Pyrazinamide
Tuberculosis is a global health problem of escalating proportions especially due to the prevalence of the acquired immunodeficiency syndrome (AIDS) that has greatly increased the incidence of the disease over the first few years. A commonly used front-line anti-tuberculosis drug is pyrazinamide (PZA) that causes dose-dependent hepatotoxicity, 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. Neither PZA nor any of its metabolites have very small HOMO-LUMO energy differences so that none is expected to be highly labile kinetically and none can be excluded from being the cause for the toxicity of PZA.
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