1- Metabolism of isoniazid – a molecular modelling analysis

Fazlul Huq

Discipline of Biomedical Science, School of Medical Sciences, Faculty of Medicine, The University of Sydney

Telephone: +61 2 9351 9522  Fax: +61 2 9351 9520  E-mail : F.Huq@fhs.usyd.edu.au

Abstract

Isoniazid (INH) is the cornerstone of therapy against tuberculosis which is a global health problem of increasing dimension. The drug is metabolized in the liver by acetylation and hydroxylation. Molecular modelling analyses based on molecular mechanics, semi-empirical (PM3) and DFT (at B3LYP/6-31G* level) calculations show that INH and its metabolites differ to some extent in their solvation energy, surface charge distribution, dipole moment, thermodynamic stability and kinetic lability. The metabolites hydrazine and acetylhydrazine are believed to be responsible for isoniazid-induced liver toxicity. However, the results of molecular modelling analyses show that both the metabolites are kinetically inert. It is possible that the compounds are spontaneously converted to more reactive metabolites pyruvate hydrazone and 1,4,5,6-tetrahydro-6-oxo-3-pyridazine carboxylic acid. The charged nature of the surface of isoniazid and its metabolites indicates that the compounds may interact with biomolecules including glutathione and nucleobases in DNA electrically. Depletion of glutathione induces cellular toxicity by compromising the antioxidant status of the cell whereas oxidation of nucleobases causes DNA damage.  It also explains why the molecules are soluble in water.

Key words: Isoniazid, tuberculosis, acetylation, molecular modelling

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