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Carcinogenesis, Vol. 22, No. 4, 553-557, April 2001
© 2001 Oxford University Press

ACCELERATED PAPER

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

Ian N.H. White1,4, Philip Carthew1,1, Reginald Davies1, Jerry Styles1, Karen Brown1,2, John E. Brown1,3, Lewis L. Smith1 and Elizabeth A. Martin1

MRC Toxicology Unit, Hodgkin Building, Lancaster Road, Leicester, LE1 9HN, UK

It is now generally accepted that activation of tamoxifen occurs as a result of metabolism to {alpha}-hydroxytamoxifen. In this study, {alpha}-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 {alpha}-hydroxytamoxifen DNA adducts were similar to those seen following the administration of tamoxifen. However, after rats were treated with {alpha}-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 {alpha}-hydroxytamoxifen was given to female {lambda}/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 {alpha}-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.


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T. Chen, G. Gamboa da Costa, M.M. Marques, S. D. Shelton, F. A. Beland, and M. G. Manjanatha
Mutations induced by {alpha}-hydroxytamoxifen in the lacI and cII genes of Big Blue transgenic rats
Carcinogenesis, October 1, 2002; 23(10): 1751 - 1758.
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