A molecular modelling study on the human cytochrome P450-mediated metabolism of tamoxifen is reported. Using three-dimensional models of human P450s constructed from the bacterial crystal structure template, P450bm3 (CYP102), the likely mode of substrate binding is demonstrated, which is consistent with the known positions of metabolism in tamoxifen. In particular, the CYP102-derived structures of CYP3A4, CYP2D6 and CYP2C9 are able to rationalize the routes of tamoxifen metabolism reported in human subjects. The implications for potential toxicity of tamoxifen in man is discussed in the light of these findings.

Anticarcinogenic Agents↗

PubMed1996

Interaction of chemopreventive agents with hormone receptors.

Our understanding of the mechanisms by which chemopreventive agents interact with hormone receptors is clearly important both to current strategies for the treatment and prevention of cancer and to future endeavours of rational drug design, perhaps aided by computer-based molecular modelling. This chapter focuses on the importance of the interaction of the nonsteroidal antiestrogen drug tamoxifen (widely used in the treatment of breast cancer and currently being proposed for the prevention of breast cancer) with the estrogen receptor to its mode of action. The improved efficacy of new tamoxifen derivatives and of the steroidal pure estrogen antagonists is also considered, and the importance of hormone-receptor mutations in the development of drug resistance in cancer cells is discussed.

Anticarcinogenic Agents↗

PubMed1995

Nitric oxide and oxygen radicals: a question of balance.

The production of superoxide and nitric oxide individually has been associated with the development of several diseases but only recently has it been realised that interactions between them may also be important in disease pathology. The central hypothesis which is emerging is that the balance between nitric oxide and superoxide generation is a critical determinant in the aetiology of many human diseases including atherosclerosis, neurodegenerative disease, ischaemia-reperfusion and cancer. These ideas are discussed in this short overview and placed in the context of the current and future status of therapies which could modulate the balance between nitric oxide and superoxide.

Cardiovascular Diseases↗

PubMed1995

DNA damage and cancer: measurement and mechanism.

There is currently great interest in the possible role of reactive nitrogen species and reactive oxygen species in causing DNA damage that leads to cancer. It appears likely that certain reactive oxygen species can act as complete carcinogens. However, the development of human cancer will depend on other factors such as the extent of DNA damage, antioxidant levels and DNA repair systems. The true picture will only be seen if we have reliable and sensitive techniques for the measurement of DNA damage. In this article we outline various methods for measuring DNA damage base, with special emphasis on HPLC and GC-MS based systems.

8-Hydroxy-2'-Deoxyguanosine↗

PubMed1995

Taking tamoxifen to heart.

Explore the source record for details and available documents.

Animals↗