The structural mimicry of membrane sterols by tamoxifen: evidence from cholesterol coefficients and molecular-modelling for its action as a membrane anti-oxidant and an anti-cancer agent.
The anti-cancer drug tamoxifen is a potent inhibitor of lipid peroxidation induced by Fe(III)-ascorbate in ox-brain phospholipid liposomes. Similar anti-oxidant effects, but with varying potencies, are also shown by 4-hydroxy-tamoxifen, cholesterol, ergosterol and 17-beta-oestradiol. We now describe a computer-graphic fitting technique that demonstrates a structural similarity between the five compounds. In addition, we have quantified the differences (relative to cholesterol) between the anti-oxidant activities of the compounds in terms of a novel expression referred to here as the cholesterol coefficient (Cc) Finally, we discuss how the inhibitory effect of tamoxifen on lipid peroxidation may result from a membrane stabilization that is associated with a decrease in membrane fluidity. This action may be related to the anti-proliferative effect exerted by tamoxifen on cancer and fungal cells.
Wiseman
H
H
Department of Biochemistry, King's College London, U.K.
Cannon
M
M
Arnstein
H R
HR
Barlow
D J
DJ
D000935:Antifungal Agents / Q000737:chemistry / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology; D000975:Antioxidants / Q000737:chemistry* / Q000494:pharmacology; D002784:Cholesterol / Q000737:chemistry / Q000494:pharmacology; D003196:Computer Graphics; D003198:Computer Simulation; D004875:Ergosterol / Q000737:chemistry / Q000494:pharmacology; D004958:Estradiol / Q000737:chemistry / Q000494:pharmacology; D015227:Lipid Peroxidation / Q000187:drug effects; D008081:Liposomes / Q000737:chemistry; D008958:Models, Molecular; D013329:Structure-Activity Relationship; D013629:Tamoxifen / Q000031:analogs & derivatives / Q000737:chemistry* / Q000494:pharmacology
D000935:Antifungal Agents; D000970:Antineoplastic Agents; D000975:Antioxidants; D008081:Liposomes; D013629:Tamoxifen; C016601:afimoxifene; D004958:Estradiol; D002784:Cholesterol; D004875:Ergosterol