title: Interindividual variation in the isomerization of 4-hydroxytamoxifen by human liver microsomes: involvement of cytochromes P450.
abstract: Tamoxifen and its metabolite 4-hydroxytamoxifen can both exist as geometrical isomers. Trans-tamoxifen is an oestrogen receptor antagonist and is used for the treatment of breast cancer. Trans-4-hydroxytamoxifen is 100 times more anti-oestrogenic than trans-tamoxifen. The cis isomers of tamoxifen and 4-hydroxytamoxifen are oestrogenic and weakly anti-oestrogenic or oestrogenic respectively. Both isomers of 4-hydroxytamoxifen 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 tamoxifen therapy. We have investigated the isomerization of 4-hydroxytamoxifen by human liver microsomes and whether it is mediated by cytochromes P450. Microsomes from five of the 12 livers examined catalysed the interconversion of trans- and cis-4-hydroxytamoxifen (0.52 microM) when incubated for 40 min with an NADPH-generating system. Between 51 and 64% conversion of trans-4-hydroxytamoxifen was observed. Cis-4-hydroxytamoxifen was also converted to trans-4-hydroxytamoxifen (range 22-27%). Incubations with control, heat-treated microsomes resulted in approximately 1% isomerization of trans-4-hydroxytamoxifen. The extent of isomerization of trans- to cis-4-hydroxytamoxifen observed in microsomes from the other seven livers (range 2-8%) did not greatly exceed that seen in heat-inactivated microsomes. Enzymatic isomerization required NADPH and was inhibited by SKF 525A and ketoconazole, indicating the involvement of cytochromes P450. Enzymatic isomerization of trans-tamoxifen and trans-droloxifene (the 3-hydroxy synthetic analogue of tamoxifen) was not observed. These findings may have implications for the safe and effective use of tamoxifen.
authors.affiliation: University of Sheffield, Department of Medicine and Pharmacology, Royal Hallamshire Hospital, UK.
authors.forename: M L
authors.initials: ML
authors.lastname: Williams
authors.forename: M S
authors.initials: MS
authors.lastname: Lennard
authors.forename: I J
authors.initials: IJ
authors.lastname: Martin
authors.forename: G T
authors.initials: GT
authors.lastname: Tucker
mesh_terms: D000328:Adult; D001711:Biotransformation; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D004351:Drug Resistance; D005260:Female; D014644:Genetic Variation; D006801:Humans; D007536:Isomerism; D007654:Ketoconazole / Q000494:pharmacology; D008297:Male; D008862:Microsomes, Liver / Q000201:enzymology*; D008875:Middle Aged; D009249:NADP / Q000502:physiology; D011335:Proadifen / Q000494:pharmacology; D013629:Tamoxifen / Q000031:analogs & derivatives* / Q000378:metabolism
chemical_list: D065607:Cytochrome P-450 Enzyme Inhibitors; D013629:Tamoxifen; C038345:droloxifene; C016601:afimoxifene; D009249:NADP; D003577:Cytochrome P-450 Enzyme System; D011335:Proadifen; D007654:Ketoconazole