Metabolism of tamoxifen by isolated rat hepatocytes. Identification of the glucuronide of 4-hydroxytamoxifen.
Metabolism of 4-hydroxytamoxifen by hepatocytes isolated from rats administered with phenobarbital and examination by TLC of the components not extractable into ethyl acetate revealed 4-hydroxytamoxifen beta-glucuronide; its identity was confirmed by comparison of its 1H NMR spectrum with that of synthetic material. This conjugate was also formed on metabolism of tamoxifen. It bound to cytosolic oestrogen receptors with only one thousandth the affinity of 4-hydroxytamoxifen and gave a correspondingly very weak inhibition of growth of the MCF-7 human breast cancer cell line. Therefore, in contrast to reported observations on the 3-glucuronide of oestradiol, the MCF-7 cells were unable to hydrolyse 4-hydroxytamoxifen glucuronide and on this evidence, formation of this metabolite is solely a deactivation pathway.
McCague
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Drug Development Section, Cancer Research Campaign Laboratory, Institute of Cancer Research, Sutton, Surrey, U.K.
Parr
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IB
Leclercq
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G
Leung
O T
OT
Jarman
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M
D000818:Animals; D004354:Drug Screening Assays, Antitumor; D004965:Estrogen Antagonists / Q000378:metabolism*; D006801:Humans; D066298:In Vitro Techniques; D008099:Liver / Q000378:metabolism*; D008297:Male; D051381:Rats; D011919:Rats, Inbred Strains; D011960:Receptors, Estrogen / Q000378:metabolism*; D013629:Tamoxifen / Q000031:analogs & derivatives / Q000378:metabolism*; D014407:Tumor Cells, Cultured
D004965:Estrogen Antagonists; D011960:Receptors, Estrogen; D013629:Tamoxifen; C016601:afimoxifene