Comparisons of the binding of [14C]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 32P-postlabelled adducts in rat liver DNA and the development of liver tumours. With the use of accelerator mass spectrometry, [14C]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 [14C]radioactivity while > 80% appeared as non-polar products. In contrast, when animals were given an equivalent dose of [14C]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.
White
I N
IN
MRC Toxicology Unit, University of Leicester, UK.
Martin
E A
EA
Mauthe
R J
RJ
Vogel
J S
JS
Turteltaub
K W
KW
Smith
L L
LL
D000818:Animals; D001711:Biotransformation; D002851:Chromatography, High Pressure Liquid; D002855:Chromatography, Thin Layer; D004247:DNA / Q000378:metabolism*; D018736:DNA Adducts / Q000032:analysis / Q000378:metabolism*; D004249:DNA Damage; D005260:Female; D005914:Globins / Q000378:metabolism; D006801:Humans; D008099:Liver / Q000378:metabolism*; D013058:Mass Spectrometry; D051379:Mice; D008815:Mice, Inbred Strains; D008862:Microsomes, Liver / Q000378:metabolism; D011485:Protein Binding; D051381:Rats; D011916:Rats, Inbred F344; D013629:Tamoxifen / Q000378:metabolism*; D017312:Toremifene / Q000378:metabolism*
D018736:DNA Adducts; D013629:Tamoxifen; D017312:Toremifene; D005914:Globins; D004247:DNA