Short-term dosing of alpha-hydroxytamoxifen results in DNA damage but doesnot lead to liver tumours in female Wistar/Han rats

It is now generally accepted that activation of tamoxifen occurs as a resul t of metabolism to alpha -hydroxytamoxifen. In this study, a-hydroxytamoxif en was given to female Wistar/Han rats (0.103 or 0.0103 mmol/kg, intraperit oneally, daily for 5 days). This resulted in liver DNA damage, determined b y P-32-post-labelling, of 3333 +/- 795 or 343 +/- 68 adducts/10(8) nucleoti des, respectively (mean +/- SD, n = 4). Following HPLC separation, the rete ntion times of the major alpha -hydroxytamoxifen DNA adducts were similar t o those seen following the administration of tamoxifen, However, after rats were treated with alpha -hydroxytamoxifen (0.103 mmol/kg) for 5 days and t he 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-fo ld 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 -h ydroxytamoxifen, is not sufficient to initiate liver tumours even with phen obarbital promotion. As with tamoxifen, long-term exposure may be required to allow promotion and progression of transformed cells.