ALTERATIONS OF DRUG-METABOLIZING AND ANTIOXIDANT ENZYME-ACTIVITIES DURING TAMOXIFEN-INDUCED HEPATOCARCINOGENESIS IN THE RAT

The triphenylethylene drug tamoxifen is a hepatocarcinogen in rats, ha s genotoxic potential and may produce carcinoma of the endometrium in humans, while the structurally closely related toremifene has no carci nogenic or genotoxic potential. We have investigated the effects of lo ng-term treatment with tamoxifen and toremifene on the activities of d rug metabolizing and antioxidant enzymes in rat liver. Female Sprague- Dawley rats were dosed with equimolar doses of tamoxifen (11.3 and 45 mg/kg) and toremifene (12 and 48 mg/kg) for 12 months and were killed after 2 days, 5 weeks, 3, 6 and 12 months of treatment. After 12 month s most rats treated with the high dose of tamoxifen had hyperplastic n odules and hepatocellular carcinomas, while in rats given toremifene o r the low dose of tamoxifen, only foci were observed. A striking, obse rvation was strong inhibition of the hexose monophosphate shunt (HMS) by tamoxifen and toremifene, which, except in the group given the high dose of tamoxifen, lasted throughout the treatment period. Both antie strogens induced susceptibility to oxidative stress, as indicated by d ecreased hepatic contents of reduced glutathione and by increased pero xidation potential of microsomal preparations. The activity of glutath ione S-transferase was permanently induced by the high dose of tamoxif en from 5 weeks onwards and was greater in tamoxifen-induced liver tum ors than in corresponding macroscopically normal tissue. Similarly, th e activity of HMS was elevated by the high dose of tamoxifen at the la test time points, and a further elevation was seen in tamoxifen-induce d liver tumors. No such alteration in glutathione S-transferase or HMS activity was seen in animals treated with toremifene or with the low dose of tamoxifen. In conclusion, tamoxifen and toremifene differ mark edly with respect to production of liver tumors, and this difference i n hepatocarcinogenic potential is reflected in differential effects on glutathione-S-transferase and HMS activities in rat liver.