H-rasActivation Is an Early Event in the Ptaquiloside-Induced Carcinogenesis: Comparison of Acute and Chronic Toxicity in Rats

Abstract

Bracken fern (Pteridiumspp.) produces cancer of the urinary bladder and oesophagus in grazing animals and is a suspected human carcinogen. The carcinogenic principle ptaquiloside (PT), when activated to a dienone (APT), forms DNA adducts which eventually leads to tumor. Two groups of female Sprague-Dawley rats were given a chronic dose of 3 mg APT weekly for 10 weeks either by intravenous (iv) tail vein or by intragastric (ig) route. A third group was given a weekly dose of 6 mg of APT for 3 weeks by theigroute corresponding to acute dosing. Both chronicivandigdosed animals showed ischemic tubular necrosis in the kidney but onlyivdosed animals developed adenocarcinomas of the mammary glands. Acutely dosediganimals produced apoptotic bodies in the liver, necrosis of blood cell precursors in the bone marrow and ischemic tubular necrosis in the kidney but they did not develop tumors. No mutations were found in the H-rasandp53genes in the mammary glands of either theigrats or the tumor-bearingivrats. However, the mammary glands of a fourth group of rats, which received APT byivand killed before tumor development, carried Pu to Pu and Pu to Py double mutations in codons 58 and 59 of H-ras.This study indicates that the route of administration plays a role in the nature of the disease expression from ptaquiloside exposure. In addition to confirming the role of APT in the PT-induced carcinogenesis our finding suggests that activation of H-rasis an early event in the PT-carcinogenesis model.