Journal Article

Short-term dosing of α-hydroxytamoxifen results in DNA damage but does not lead to liver tumours in female Wistar/Han rats

Ian N.H. White, Philip Carthew, Reginald Davies, Jerry Styles, Karen Brown, John E. Brown, Lewis L. Smith and Elizabeth A. Martin

in Carcinogenesis

Volume 22, issue 4, pages 553-557
Published in print April 2001 | ISSN: 0143-3334
Published online April 2001 | e-ISSN: 1460-2180 | DOI: http://dx.doi.org/10.1093/carcin/22.4.553
Short-term dosing of α-hydroxytamoxifen results in DNA damage but does not lead to liver tumours in female Wistar/Han rats

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It is now generally accepted that activation of tamoxifen occurs as a result of metabolism to α-hydroxytamoxifen. In this study, α-hydroxytamoxifen was given to female Wistar/Han rats (0.103 or 0.0103 mmol/kg, intraperitoneally, daily for 5 days). This resulted in liver DNA damage, determined by 32P-post-labelling, of 3333 ± 795 or 343 ± 68 adducts/108 nucleotides, respectively (mean ± SD, n = 4). Following HPLC separation, the retention times of the major α-hydroxytamoxifen DNA adducts were similar to those seen following the administration of tamoxifen. However, after rats were treated with α-hydroxytamoxifen (0.103 mmol/kg) for 5 days and the animals kept for up to 13 months, no liver tumours developed (0/7 rats), even with phenobarbital promotion (0/5 rats). GST-P foci were detected in the liver, but only after 13 months was their number or area significantly increased over the corresponding controls. When α-hydroxytamoxifen was given to female λ/lacI transgenic rats (0.103 mmol/kg orally for 10 days) and the animals killed 46 days later, there was an approximate 1.8-fold increase in mutation frequency but no significant increase in G:C to T:A transversions as described after tamoxifen treatment. It is concluded that DNA damage alone, resulting from the short-term administration of α-hydroxytamoxifen, is not sufficient to initiate liver tumours even with phenobarbital promotion. As with tamoxifen, long-term exposure may be required to allow promotion and progression of transformed cells.

Keywords: BrdU, 5-bromodeoxyuridine; GST-P, placental form of glutathione S-transferase; PB, phenobarbital; PCNA, proliferating cell nuclear antigen.

Journal Article.  3928 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

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