Tamoxifen (and 4-hydroxytamoxifen), a nonsteroidal triphenylethylene anties
trogenic drug widely used in the treatment of breast cancer, interacts stro
ngly with the respiratory chain of isolated rat liver mitochondria. The dru
g acts as both an uncoupling agent and a powerful inhibitor of electron tra
nsport. Tamoxifen brings about a collapse of the membrane potential. Enzyma
tic assays and spectroscopic studies indicate that tamoxifen inhibits elect
ron transfer in the respiratory chain at the levels of complex III (ubiquin
ol-cytochrome-c reductase) and, to a lesser extent, of complex IV (cytochro
me-c oxidase). The activities can be restored by the addition of diphosphat
idylglycerol, a phospholipid implicated in the functioning of the respirato
ry chain complexes.