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

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 + or - 795 or 343 + or - 68 adducts/108 nucleotides, respectively (mean + or - 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.