senkirkine 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

The carcinogenicity of the pyrrolizidine alkaloids senkirkine and symphytine was studied in male inbred ACI rats. Animals were divided into 3 groups: Group I received ip injections of freshly prepared senkirkine at a dose of 10% of the median lethal dose (LD50) twice weekly for 4 weeks and then once a week for 52 weeks. Group II received ip injections of symphytine at a dose of 10% of the LD50 by the same injection schedule as in group I. The control group was given ip injections of a 0.9% NaCl solution following the same injection schedule as in experimental groups. All group I rats survived for more than 290 days after the start of injections, and 9 of 20 rats developed liver cell adenoma. All group II animals survived for more than 330 days after the start of injections. Of 20 rats, 4 had liver tumors, 3 had hemangioendothelial sarcomas, and 1 had liver cell adenoma. The hemangioendothelial sarcomas showed metastasis in the lungs of 2 rats. The control group had no liver tumors.

Topics: Animals; Hemangioendothelioma; Liver Neoplasms; Liver Neoplasms, Experimental; Male; Neoplasms, Experimental; Pyrrolizidine Alkaloids; Rats; Rats, Inbred ACI; Time Factors