3. Molecular modelling analysis of the metabolism of tamoxifen

Fazlul Huq

School of Biomedical Sciences, Faculty of Health Sciences, The University of Sydney, f.huq@fhs.usyd.edu.au.

(Received 20  November 2005; accepted 23 January 2006)

Abstract: Tamoxifen (T) is a nonsteroidal antiestrogen that has become the agent of choice in the treatment and prevention of breast cancer. Chemically, T is z-1-(4-(2-dimethylaminoethoxy) phenyl)-1,2-diphenyl-1-butene). The main concern regarding treatment with T in humans is the increased risk of endometrial cancers and blood clots. The major metabolic pathways for the metabolism of T involve N-demethylation, aromatic hydroxylation, -hydroxylation of the side chain and N-oxidation. Metabolism of T by monooxygenases produces reactive intermediates that bind with protein and DNA. Molecular modelling analyses based on molecular mechanics, semi-empirical (PM3) and DFT (at B3LYP/6-31G* level) calculations using the program Spartan ’02 show that T and its metabolites differ in solvation energy, surface charge distribution, dipole moment, thermodynamic stability and kinetic lability. For T and most of its metabolites, neutral green regions predominate so that the compounds would have low solubility in water and hence a low clearance rate. Closeness or overlap of regions of negative electrostatic potential and HOMOs having high electron density at some positions e.g. amino nitrogen and ethoxy oxygen atoms, give further support to the idea that the positions may be subject to electrophilic attack. Quinone methide (QM), which is believed to be one of the metabolites responsible for DNA damage, has the smallest LUMO-HOMO energy difference indicating that it would be most kinetically labile. Also, QM has large heat of formation (32.46 kcal mol^-1) as compared to that for its parent metabolite FHT (-1.90 kcal mol^-1) indicating that QM is likely to be thermodynamically unstable as well. Another metabolite TFET (3,4-epoxytamoxifen) which is also believed to be responsible for DNA damage has large heat of formation as compared to that of its parent metabolite TFDHT (3,4-dihydroxytamoxifen) indicating that the compound may also be thermodynamically unstable. Also, TFET has a small LUMO-HOMO energy difference indicating that the compound may be kinetically labile as well.

The results of the analyses support the idea kinetic lability is likely to be an important factor in determining toxicity of xenobiotics and their metabolites.

Key words: Tamoxifen, CYP, TNO, QM, molecular modelling

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