Comparison of DNA reactivity of the polyphenylethylene hormonal agents diethylstilbestrol, tamoxifen and toremifene in rat and hamster liver.
The polyphenylethylene estrogenic drug diethylstilbestrol and a structural analogue tamoxifen have been found to be hepatocarcinogenic in female rats, whereas another analogue, toremifene, did not induce liver tumors. The 32P post-labelling technique for detection of DNA adducts was used to investigate the DNA reactivity of these three hormonal agents in the livers of female Sprague-Dawley rats and Syrian hamsters. Adducts were quantified using a radioanalytic imaging system in comparison with the standard Cerenkov assay. With administration of the chemicals at several doses by daily gavage to rats for 10 days and to hamsters for 7 days, tamoxifen was found to produce five adducts in rat liver and six adducts in hamster liver. The amounts of adducts were dose related from 10 to 90 mumol/kg per day in rats and from 17 to 160 mumol/kg per day in hamsters. The two methods of quantification yielded comparable results. Under these conditions, neither toremifene nor diethylstilbestrol produced adducts in rats and diethylstilbestrol produced none in hamsters. We conclude that tamoxifen is highly DNA reactive in the species studied and that this is likely to be involved in its strong carcinogenicity in rat liver.
Montandon
F
F
American Health Foundation, Valhalla, NY 10595.
Williams
G M
GM
D000818:Animals; D002273:Carcinogens / Q000378:metabolism* / Q000633:toxicity; D006224:Cricetinae; D004247:DNA / Q000378:metabolism*; D004054:Diethylstilbestrol / Q000378:metabolism / Q000633:toxicity*; D005260:Female; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008647:Mesocricetus; D051381:Rats; D017207:Rats, Sprague-Dawley; D013629:Tamoxifen / Q000378:metabolism / Q000633:toxicity*; D017312:Toremifene / Q000378:metabolism / Q000633:toxicity*
D002273:Carcinogens; D013629:Tamoxifen; D004054:Diethylstilbestrol; D017312:Toremifene; D004247:DNA