Pancreatic islet-cell and other tumors in rats given heliotrine, a monoester pyrrolizidine alkaloid, and nicotinamide

Three rats of six males, surviving 22 to 27.5 months after one or two intragastric doses of the monoester pyrrolizidine alkaloid, heliotrine (230 mg/kg body weight), and pretreatment with nicotinamide (350 mg/kg body weight) by pretreatment with nicotinamide (350 mg/kg body weight) by i.p. injections, developed pancreatic islet-cell tumors, accompanied in one of the rats by transitory cell papillomas of the urinary bladder and interstitial testicular tumors and in another by a hepatoma. The lesions in the livers showed progression from megalocytosis, to microscopic hepatocellular hyperplasia, to increasingly larger nodules and hepatoma. One rat, given heliotrine, but no nicotinamide, also developed adenoma of the pancreatic islet cells. Adenomas of the pituitary were present among the experimental and also among the control rats killed between 19 and 27.5 months after the beginning of the experiment, and they are not likely to have been caused by the alkaloid. Heliotrine, in which the crucial double bond in the pyrrolizidine moiety is sterically hindered, appears to be less readily sequestered by the liver and also to affect other organs. Alkylation of nicotinamide at the N-1 position prevents its being reused for coenzyme biosynthesis. Hence, pretreatment of rats with large doses of nicotinamide prevents the depletion of nicotinamide adenine dinucleotide coenzymes and liver necrosis in rats given heliotrine (230 mg/kg body weight).