Comparisons of the binding of [C-14]radiolabelled tamoxifen or toremifene to rat DNA using accelerator mass spectrometry

Tamoxifen, widely used as adjuvant therapy in the treatment of breast cancer, is now undergoing trials as a cancer chemopreventative agent. Previous work has shown an association between P-32-postlabelled adducts in rat liver DNA and the development of liver tumours. With the use of accelerator mass spectrometry, [C-14]tamoxifen was shown to bind to liver DNA of female rats in a dose-dependent manner and was linear over 0.1-1 mg/kg, compatible with the therapeutic dose used in women (20 mg/person per day). Radiolabel could also be detected in extrahepatic organs, including reproductive and GI-tract, where levels were about 18 and 46%, respectively those seen in liver. Following enzymatic hydrolysis of liver DNA, normal nucleotides by HPLC showed < 2% incorporation of the [C-14]radioactivity while > 80% appeared as non-polar products. In contrast, when animals were given an equivalent dose of [C-14]toremifene, binding to DNA was an order of magnitude lower than that seen with tamoxifen and no evidence of non-polar adducted nucleotides following HPLC. However, in vitro, using human, rat or mouse liver microsomal preparations;; NADPH-dependent binding of both toremifene and tamoxifen to calf thymus DNA could be demonstrated, suggesting that under favourable circumstances toremifene is capable of undergoing conversion to reactive intermediates. (C) 1997 Elsevier Science Ireland Ltd.