lasiocarpine and Liver-Neoplasms

Pyrrolizidine alkaloids (PA) are secondary plant metabolites that occur as food and feed contaminants. Acute and subacute PA poisoning can lead to severe liver damage in humans and animals, comprising liver pain, hepatomegaly and the development of ascites due to occlusion of the hepatic sinusoids (veno-occlusive disease). Chronic exposure to low levels of PA can induce liver cirrhosis and liver cancer. However, it is not well understood which transcriptional changes are induced by PA and whether all hepatotoxic PA, regardless of their structure, induce similar responses. Therefore, a 28-day subacute rat feeding study was performed with six structurally different PA heliotrine, echimidine, lasiocarpine, senecionine, senkirkine, and platyphylline, administered at not acutely toxic doses from 0.1 to 3.3 mg/kg body weight. This dose range is relevant for humans, since consumption of contaminated tea may result in doses of ~ 8 µg/kg in adults and cases of PA ingestion by contaminated food was reported for infants with doses up to 3 mg/kg body weight. ALT and AST were not increased in all treatment groups. Whole-genome microarray analyses revealed pronounced effects on gene expression in the high-dose treatment groups resulting in a set of 36 commonly regulated genes. However, platyphylline, the only 1,2-saturated and, therefore, presumably non-hepatotoxic PA, did not induce significant expression changes. Biological functions identified to be affected by high-dose treatments (3.3 mg/kg body weight) comprise cell-cycle regulation associated with DNA damage response. These functions were found to be affected by all analyzed 1,2-unsaturated PA.In conclusion, 1,2-unsaturated hepatotoxic PA induced cell cycle regulation processes associated with DNA damage response. Similar effects were observed for all hepatotoxic PA. Effects were observed in a dose range inducing no histopathological alterations and no increase in liver enzymes. Therefore, transcriptomics studies identified changes in expression of genes known to be involved in response to genotoxic compounds at PA doses relevant to humans under worst case exposure scenarios.

Topics: Animals; DNA Damage; Gene Expression; Humans; Liver; Liver Neoplasms; Plants; Pyrrolizidine Alkaloids; Rats; Structure-Activity Relationship

1 Hyperplastic liver nodules were induced in F-344 rats by concurrent administration of lasiocarpine (50 ppm in diet) and thioacetamide (50 mg/kg body weight twice weekly) for 15 weeks. 2 The effect of carbohydrate calorie and total calorie restriction on the fate of hyperplastic liver nodules was examined. 3 The incidence of hepatocellular carcinoma was the same in all groups of rats irrespective of the magnitude of carbohydrate calorie restriction and 50% total calorie restriction. 4 These studies demonstrate that carbohydrate or total calorie restriction has no effect on the progression of hyperplastic nodules to hepatocellular carcinoma.

Topics: Acetamides; Animals; Body Weight; Carcinogens; Diet; Dietary Carbohydrates; Energy Intake; Hyperplasia; Liver; Liver Neoplasms; Male; Pyrrolizidine Alkaloids; Rats; Rats, Inbred F344; Thioacetamide

Lasiocarpine, a pyrrolizidine alkaloid, was fed at a dietary concentration of 50/10(6) for 55 weeks, to 20 male F-344 rats. Malignant tumours developed in 17/20 animals between 48 and 59 weeks. Forty-five percent (9/20) developed angiosarcomas of the liver and 35% (7/20) had hepatocellular carcinomas. Other tumours included malignant adnexas tumour of the skin (1 rat) and lympohoma (1 rat). Lung metastases were observed in 4 animals with angiosarcoma of the liver and one animal with hepatocellular carcinoma. From one animal, angiosarcoma was successfully transplanted through 4 generations.

Topics: Animals; Carcinogens; Carcinoma, Hepatocellular; Hemangiosarcoma; Liver Neoplasms; Male; Neoplasms; Plants, Toxic; Pyrrolizidine Alkaloids; Rats; Rats, Inbred F344; Senecio