7- Molecular modelling analysis of the metabolism of raloxifene

Fazlul Huq and Shahnaz Al-Qassab

Discipline of Biomedical Science, Faculty of Medicine, The University of Sydney

 Address reprint requests and correspondences to:

Dr. Fazlul Huq, Discipline of Biomedical Science,

Faculty of Medicine, C42, The University of Sydney,

PO Box 170, Lidcombe, NSW 1825, Australia.

Raloxifene is a second generation selective estrogen receptor modulator that is effective in the treatment of osteoporosis in postmenopausal women. Currently it is being evaluated for treatment against breast cancer that remains a major health problem as incidence rates continue to rise despite recent improvements in mortality rates. However, the quinone metabolites of RFN namely RFN-DQM and RFN-OQ (like those of tamoxifen) are expected to be electrophilic and redox active that can cause DNA damage directly through the formation of DNA adducts and indirectly through the generation of reactive oxygen species (ROS) that can oxidize DNA. Molecular modelling analyses based on molecular mechanics, semi-empirical (PM3) and DFT (at B3LYP/6-31G* level) calculations show that RFN and its metabolites differ in solvation energy, surface charge distribution, dipole moment and kinetic lability. RFN-OQ is found to have the smallest LUMO-HOMO energy difference indicating that the metabolite would be most reactive kinetically. However, the metabolite does not appear to abound in electron-deficient regions as much as the third most reactive metabolite RFN-DQM. Because the surface of RFN-DQM abounds in electron-deficient regions, it may be subject to nucleophilic attack by glutathione and nucleobases in DNA, thus causing depletion of cellular glutathione and oxidation of nucleobases. This means that the toxicity of RFN may be mediated via the formation of electrophilic metabolite RFN-DQM.

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