Initiating activity of the anti-estrogen tamoxifen, but not toremifene in rat liver

A striking difference between two structurally related anti-estrogenmedicines is that tamoxifen is strongly hepatocarcinogenic in the rat,whereas toremifene lacks such activity. To study the basis for thisdifference, the initiating potential of tamoxifen and toremifene werestudied by measurement of rapid induction of hepatocellular altered foci(HAF) that express placental-type glutathione S-transferase in the liversof female Sprague-Dawley (S-D) rats and female Fischer 344 (F344) rats.Both agents were administered by gavage at equimolar doses up to a dosethat produced marked weight gain suppression. In rats given the high doseof 40 mg/kg per day tamoxifen continuously for 36 weeks, 75% of S-D ratsdeveloped liver neoplasms, in contrast to only 10% of F344 rats. In the S-Dstrain, tamoxifen produced a tendency to increased HAF at 2 weeks at thedose of 40 mg/kg per day and by 12 weeks, a dose-related increase wasevident. In contrast, toremifene induced no HAF even at the equimolar highdose of 42.4 mg/kg per day for 12 weeks. The induction of HAF by tamoxifenwas less in the F344 rats. Neither agent elicited increases inhepatocellular proliferation in S-D or F344 rats. When phenobarbital wasadministered for 24 weeks as a promoting agent after the anti-estrogens,S-D rats given tamoxifen at 20 mg/kg per day for 12 weeks, developed liverneoplasms, but not F344 rats or rats of either strain given even a higherdose (42.4 mg/kg) of toremifene. Thus, tamoxifen has initiating activity inthese rat strains whereas toremifene does not.