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 (32)P-post-labelling, of 3333 +/- 795 or 343 +/- 68 adducts/10(8) 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.
White
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IN
MRC Toxicology Unit, Hodgkin Building, Lancaster Road, Leicester, LE1 9HN, UK. iw6@le.ac.uk
Carthew
P
P
Davies
R
R
Styles
J
J
Brown
K
K
Brown
J E
JE
Smith
L L
LL
Martin
E A
EA
D000818:Animals; D030801:Animals, Genetically Modified; D002273:Carcinogens; D002851:Chromatography, High Pressure Liquid; D018736:DNA Adducts / Q000378:metabolism; D004249:DNA Damage; D018450:Disease Progression; D005260:Female; D005982:Glutathione Transferase / Q000378:metabolism; D022781:Hepatocytes / Q000378:metabolism; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008113:Liver Neoplasms / Q000139:chemically induced* / Q000235:genetics*; D009154:Mutation; D010634:Phenobarbital; D018809:Proliferating Cell Nuclear Antigen / Q000096:biosynthesis; D051381:Rats; D017208:Rats, Wistar; D013629:Tamoxifen / Q000009:adverse effects* / Q000031:analogs & derivatives*; D013997:Time Factors
D002273:Carcinogens; D018736:DNA Adducts; D018809:Proliferating Cell Nuclear Antigen; C110902:alpha-hydroxytamoxifen; D013629:Tamoxifen; D005982:Glutathione Transferase; D010634:Phenobarbital