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Journal of Pharmacology and Toxicology

Year: 2006  |  Volume: 1  |  Issue: 4  |  Page No.: 299 - 316

Molecular Modelling Analysis of the Metabolism of Vinyl chloride

Fazlul Huq


Vinyl chloride is a highly toxic industrial chemical that is carcinogenic to both humans and experimental animals. It is a colourless explosive gas that is almost insoluble in water but highly soluble in fats and organic solvents. Vinyl chloride is metabolized primarily in the liver. It is believed that the human carcinogenic outcome of vinyl chloride results from its metabolic activation, catalysed by cytochrome P450 enzyme, followed by DNA binding of the reactive metabolites to form exocyclic ethanol adducts. Molecular modelling analyses based on molecular mechanics, semi-empirical (PM3) and DFT (at B3LYP/6-31G* level) calculations indicate that the long persistence of vinyl chloride in the environment is due to kinetic inertness. Although chloroethylene oxide is kinetically inert, it is thermodynamically unstable and spontaneously rearranges to more reactive metabolite chloroacetaldehyde. Relatively small LUMO-HOMO energy differences suggest that S-formylmethylcysteine, S-acetylglutathione and N-acetyl-S-(2-hydroxyethyl)cysteine would be kinetically labile and could be quite toxic but are more easily eliminated because of greater solubility in water.

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