4-Hydroxytamoxifen Gives DNA Adducts by Chemical Activation, but Not in Rat Liver Cells

• Published in: Chemical research in toxicology 1999-02, Vol.12 (2), p.151-158
• Main Authors: Osborne, Martin R, Davis, Warren, Hewer, Alan J, Hardcastle, Ian R, Phillips, David H
• Format: Article
• Language: English
• Subjects: Animals; DNA - chemistry; DNA - metabolism; DNA Adducts - analysis; DNA Adducts - metabolism; Estrogen Antagonists - chemistry; Estrogen Antagonists - metabolism; Female; Liver - cytology; Liver - metabolism; Rats; Rats, Inbred F344; Tamoxifen - analogs & derivatives; Tamoxifen - chemistry; Tamoxifen - metabolism
• ISSN: 0893-228X; 1520-5010
• DOI: 10.1021/tx980187w

The drug tamoxifen shows evidence of genotoxicity, and induces liver tumors in rats. Covalent DNA adducts have been detected in the liver of rats treated with tamoxifen, and in rat hepatocytes in culture. These arise primarily from its metabolite α-hydroxytamoxifen, and may also arise, in part, from another metabolite, 4-hydroxytamoxifen. We have prepared two model compounds for the potential reactive metabolite formed from 4-hydroxytamoxifen in rat liver. One of these was its α-acetoxy ester. This was much more reactive than that from tamoxifen, and could not be isolated in pure form. It reacted with DNA in the same way that α-acetoxytamoxifen did, to give adducts which were isolated by hydrolysis and chromatography, and identified as alkyldeoxyguanosines. The second derivative was α,β-dehydro-4-hydroxytamoxifen. This also reacts with DNA in vitro, to give the same products as those from α-acetoxy-4-hydroxytamoxifen. Reaction probably proceeds through the same resonance-stabilized carbocation in either case. However, when primary cultures of rat hepatocytes were treated with either 4-hydroxytamoxifen, 4,α-dihydroxytamoxifen, or α,β-dehydro-4-hydroxytamoxifen at a concentration of 10 μM, no adducts could be detected in their DNA by the 32P-postlabeling technique. Similarly, no adducts could be found in the liver DNA of female Fischer F344 rats treated orally (at 0.12 mmol kg-1) with the same substances. If 4-hydroxytamoxifen is metabolized to 4,α-dihydroxytamoxifen in rat liver, then either this substance is not converted to reactive esters or they are rapidly detoxified.