|
Molecular Modelling Analysis of The Metabolism of
Hydralazine
Zahed Hossain and
Fazlul Huq*
School of Biomedical
Sciences, Faculty of Health Sciences,
C42, The University of Sydney, PO Box 170, Lidcombe, NSW 1825,
E-mail :
f.huq@fhs.usyd.edu.au.
Australia
Abstract:
Hydralazine, widely used in the long term treatment of hypertension,
can cause a disease with auto immune features known as lupus
erythematosus that is characterized by connective tissue alteration
and damage similar to that found in rheumatoid arthritis. However the
molecular mechanism of toxicity due to hydralazine remains unclear.
Hydralazine is metabolized by N-acetylation, glucuronidation and
hydroxylation. Hydralazine-induced lupus occurs in individuals with a
low capacity for N-acetylation. Acetylation is the major route of
hydralazine metabolism that yields the non-toxic metabolite
3-methyl-s-triazolo[3,4-a]phthalazine.
This suggests that either the parent drug or a different metabolic
pathway is involved in the induction of lupus. Molecular modelling
analyses using semi-empirical and DFT calculations show that a number
of metabolites of hydralazine are kinetically labile with relatively
low values for HOMO-LUMO energy differences; the most labile one being
phthalazine dimer that is believed to be formed from the free radicals
produced from hydralazine. It is logical to assume that the free
radicals produced would be even more reactive that can damage DNA and
other biomolecules.
Key words:Hydralazine,
acetylation, toxicity, molecular modelling
<<< |
