INTERINDIVIDUAL VARIATION IN THE ISOMERIZATION OF 4-HYDROXYTAMOXIFEN BY HUMAN LIVER-MICROSOMES - INVOLVEMENT OF CYTOCHROMES P450

Tamoxifen and its metabolite 4-hydroxytamoxifen can both exist as geom etrical isomers. Trans-tamoxifen is an oestrogen receptor antagonist a nd is used for the treatment of breast cancer, Trans-4-hydroxytamoxife n is 100 times more anti-oestrogenic than trans-tamoxifen, The cis iso mers of tamoxifen and 4-hydroxytamoxifen are oestrogenic and weakly an ti-oestrogenic or oestrogenic respectively, Both isomers of 4-hydroxyt amoxifen have been detected in breast tumours of patients treated with trans-tamoxifen and it has been proposed that enzymatic isomerization of 4-hydroxytamoxifen occurs in vivo, resulting in resistance to tamo xifen therapy, We have investigated the isomerization of 4-hydroxytamo xifen by human liver microsomes and whether it is mediated by cytochro mes P450, Microsomes from five of the 12 livers examined catalysed the interconversion of trans- and cis-4-hydroxytamoxifen (0.52 mu M) when incubated for 40 min with an NADPH-generating system, Between 51 and 64% conversion of trans-4-hydroxytamoxifen was observed, Cis-4-hydroxy tamoxifen was also converted to trans-4-hydroxytamoxifen (range 22-27% ), Incubations with control, heat-treated microsomes resulted in simil ar to 1% isomerization of trans-4-hydroxytamoxifen. The extent of isom erization of trans- to cis-4-hydroxytamoxifen observed in microsomes f rom the other seven livers (range 2-8%) did not greatly exceed that se en in heat-inactivated microsomes, Enzymatic isomerization required NA DPH and was inhibited by SKF 525A and ketoconazole, indicating the inv olvement of cytochromes P450, Enzymatic isomerization of trans-tamoxif en and trans-droloxifene (the 3-hydroxy synthetic analogue of tamoxife n) was not observed, These findings may have implications for the safe and effective use of tamoxifen.