The Hepatic Endothelial Carcinogen Riddelliine Induces Endothelial Apoptosis, Mitosis, S Phase, and p53 and Hepatocytic Vascular Endothelial Growth Factor Expression after Short-Term Exposure

Nyska, Abraham

doi:10.1006/taap.2002.9485

Cited by 22 publications

(16 citation statements)

References 45 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Several DHPAs have been associated with various neoplasms [38]. However, riddelliine has been extensively studied with lifetime studies in several species, extensive characterization and descriptions of the neoplasms and proliferative lesions, and molecular and genomic studies documenting the molecular mechanisms of riddelliine-induced neoplasia [39,40,41,42]. These studies contributed to riddelliine’s classification as a potential human carcinogen [43].…”

Section: Discussionmentioning

confidence: 99%

Dehydropyrrolizidine Alkaloid Toxicity, Cytotoxicity, and Carcinogenicity

Stegelmeier

Colegate

Brown

2016

Toxins

View full text Add to dashboard Cite

Dehydropyrrolizidine alkaloid (DHPA)-producing plants have a worldwide distribution amongst flowering plants and commonly cause poisoning of livestock, wildlife, and humans. Previous work has produced considerable understanding of DHPA metabolism, toxicity, species susceptibility, conditions, and routes of exposure, and pathogenesis of acute poisoning. Intoxication is generally caused by contaminated grains, feed, flour, and breads that result in acute, high-dose, short-duration poisoning. Acute poisoning produces hepatic necrosis that is usually confirmed histologically, epidemiologically, and chemically. Less is known about chronic poisoning that may result when plant populations are sporadic, used as tisanes or herbal preparations, or when DHPAs contaminate milk, honey, pollen, or other animal-derived products. Such subclinical exposures may contribute to the development of chronic disease in humans or may be cumulative and probably slowly progress until liver failure. Recent work using rodent models suggest increased neoplastic incidence even with very low DHPA doses of short durations. These concerns have moved some governments to prohibit or limit human exposure to DHPAs. The purpose of this review is to summarize some recent DHPA research, including in vitro and in vivo DHPA toxicity and carcinogenicity reports, and the implications of these findings with respect to diagnosis and prognosis for human and animal health.

show abstract

Section: Discussionmentioning

confidence: 99%

Dehydropyrrolizidine Alkaloid Toxicity, Cytotoxicity, and Carcinogenicity

Stegelmeier

Colegate

Brown

2016

Toxins

View full text Add to dashboard Cite

show abstract

“…G:C → T:A transversion may cause the initiation of tumors in the liver of rats fed with comfrey, because it has been reported that more than half of riddelliine-induced liver hemangiosarcomas have a G → T mutation at K- ras codon 12 [37]. p53 mutation also has been detected at an early stage of riddelliine exposure [38]. Mutations are thought to be involved in carcinogenesis because the transition from a normal somatic cell to a cancer cell is due to mutations in protooncogenes, tumor suppressor genes and/or genes that function in the maintenance of genomic stability [39,40].…”

Section: Discussionmentioning

confidence: 99%

Analysis of gene expression changes in relation to toxicity and tumorigenesis in the livers of Big Blue transgenic rats fed comfrey (Symphytum officinale)

Mei

Guo

Zhang³

et al. 2006

BMC Bioinformatics

View full text Add to dashboard Cite

Background: Comfrey is consumed by humans as a vegetable and a tea, and has been used as an herbal medicine for more than 2000 years. Comfrey, however, is hepatotoxic in livestock and humans and carcinogenic in experimental animals. Our previous study suggested that comfrey induces liver tumors by a genotoxic mechanism and that the pyrrolizidine alkaloids in the plant are responsible for mutation induction and tumor initiation in rat liver.

show abstract

“…Previous studies indicate that the toxicity of riddelliine is specifically directed toward liver endothelial cells [9]. Riddelliine is activated by the rat and human hepatic P450 enzymes [4,5], and its active metabolites cause a disproportionate amount of DNA damage [9] and a disproportionate level of S-phase arrest [8] in liver endothelial cells. Following 6-week treatment with 1.0 and 2.5 mg/kg/day riddelliine, endothelial cells showed karyomegaly, cytomegaly, decreased apoptosis, more Sphase nuclei, and p53-positive nuclei, while parenchymal cells exhibited reduced mitosis, fewer S-phase nuclei, increased hypertrophy, and fatty degeneration [8].…”

Section: Discussionmentioning

confidence: 99%

“…These observations on the metabolism and target-tissue specificity for riddelliine tumorigenesis suggested that active metabolites of riddelliine interact with endothelial cells in the liver, which causes cell toxicity, followed by compensatory proliferation of DNAdamaged endothelial cells, 'fixation' of the adducts into mutations in these cells, and eventual development of hemangiosarcoma [8]. Consistent with liver endothelial cells being a specific target for riddelliine toxicity, we previously found that riddelliine-treated mice and rats had higher and more persistent DNA adduct levels in liver endothelial cells than in parenchymal cells [9].…”

Section: Introductionmentioning

confidence: 99%

Differential mutagenicity of riddelliine in liver endothelial and parenchymal cells of transgenic big blue rats

Mei

Chou

et al. 2004

Cancer Letters

View full text Add to dashboard Cite

Riddelliine is a naturally occurring pyrrolizidine alkaloid that induces liver hemangiosarcomas in rats and mice. We previously reported higher levels of DNA adducts in liver endothelial cells than in liver parenchymal cells of riddelliine-treated mice and rats [Cancer Lett. 193 (2003) 119], suggesting that the tumor specificity is due to higher levels of DNA damage in the cells that form hemangosarcomas. In the present study, we evaluated the cell-specificity of riddelliine mutagenicity in rat liver. Female transgenic Big Blue rats were treated by gavage with 0.3 mg riddelliine per kg body weight, 5 days a week for 12 weeks. One day after the last treatment, the rats were sacrificed and liver parenchymal and endothelial cell fractions were isolated and purified. DNA was extracted from the cell fractions and used to assay for mutant frequency (MF) in the cII transgene. While there was no difference in the cII MFs of liver parenchymal cells in control and riddelliine-treated rats, the cII MF of liver endothelial cells from treated rats was significantly greater than the cII MF of endothelial cells from control rats. Molecular analysis of the mutants in liver endothelial cells indicated that G:C-->T:A transversion, a mutation that is characteristically induced by riddelliine, accounted for only 9% of all mutations in control rats, but made up 17% of mutations in treated rats. In contrast, G:C-->A:T transition, the major mutation in control rats where it made up 54% of all mutations, was reduced to 40% of mutations in riddelliine-treated rats. These results suggest that the relatively high mutagenicity of riddelliine in rat liver endothelial cells may be partially responsible for the tumorigenic specificity of this agent.

show abstract

The Hepatic Endothelial Carcinogen Riddelliine Induces Endothelial Apoptosis, Mitosis, S Phase, and p53 and Hepatocytic Vascular Endothelial Growth Factor Expression after Short-Term Exposure

Cited by 22 publications

References 45 publications

Dehydropyrrolizidine Alkaloid Toxicity, Cytotoxicity, and Carcinogenicity

Dehydropyrrolizidine Alkaloid Toxicity, Cytotoxicity, and Carcinogenicity

Analysis of gene expression changes in relation to toxicity and tumorigenesis in the livers of Big Blue transgenic rats fed comfrey (Symphytum officinale)

Differential mutagenicity of riddelliine in liver endothelial and parenchymal cells of transgenic big blue rats

Contact Info

Product

Resources

About