Alterations of drug metabolizing and antioxidant enzyme activities during tamoxifen-induced hepatocarcinogenesis in the rat

The triphenylethylene drug tamoxifen is a hepatocarcinogen inrats, has genotoxic potential and may produce carcinoma of theendometrium in humans, while the structurally closely relatedtoremifene has no carcinogenic or genotoxic potential. We haveinvestigated the effects of long-term treatment with tamoxifenand toremifene on the activities of drug metabolizing and antioxidantenzymes in rat liver. Female Sprague-Dawley rats were dosedwith 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 months mostrats treated with the high dose of tamoxifen had hyperplasticnodules and hepatocellular carcinomas, while in rats given toremifeneor the low dose of tamoxifen, only foci were observed. A strikingobservation was strong inhibition of the hexose monophosphateshunt (HMS) by tamoxifen and toremifene, which, except in thegroup given the high dose of tamoxifen, lasted throughout thetreatment period. Both antiestrogens induced susceptibilityto oxidative stress, as indicated by decreased hepatic contentsof reduced glutathione and by increased peroxidation potentialof microsomal preparations. The activity of glutathione S-transferasewas permanently induced by the high dose of tamoxifen from 5weeks onwards and was greater in tamoxifen-induced liver tumorsthan in corresponding macroscopically normal tissue. Similarly,the activity of HMS was elevated by the high dose of tamoxifenat the latest time points, and a further elevation was seenin tamoxifen-induced liver tumors. No such alteration in glutathioneS-transferase or HMS activity was seen in animals treated withtoremifene or with the low dose of tamoxifen. In conclusion,tamoxifen and toremifene differ markedly with respect to productionof liver tumors, and this difference in hepatocarcinogenic potentialis reflected in differential effects on glutathione-S-transferaseand HMS activities in rat liver.