| Final report on carcinogens background document for riddelliine. | |
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MedLine Citation:
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PMID: 20737008 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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INTRODUCTION: Riddelliine is a pyrrolizidine alkaloid (PA) of the macrocyclic diester class. PAs are esters of unsaturated basic alcohols (necine bases) and necic acids and have been estimated to be present in approximately 6,000 plant species in 12 families distributed throughout the temperate and tropical regions of the world. Riddelliine was nominated by the National Institute of Environmental Health Sciences for possible listing in the Report on Carcinogens based on the results of a National Toxicology Program bioassay that reported clear evidence of carcinogenic activity in rats and mice. HUMAN EXPOSURE: Riddelliine and riddelliine N-oxide (a metabolite of riddelliine that can be converted back to riddelliine) occur in plants of the genus Senecio that are found in sandy desert areas of the western United States and other parts of the world. At least 15 Senecio species have been identified that are used in herbal medicines or possibly as food worldwide. Herbal products containing PAs, including several herbal teas, have been extensively documented as causing toxicity in humans. Two cases of accidental poisoning of infants were reported from the southwestern United States in which Senecio longilobus, a species known to contain riddelliine as well as seneciphylline, senecionine, and retrorsine, was accidentally used to prepare an herbal tea known as gordolobo yerba. Senecio species containing riddelliine are not generally used as food plants in the United States, but ingestion by humans could result from direct contamination of foodstuffs by parts of Senecio plants or from indirect introduction of the alkaloid through products derived from animals that have fed on the plants. Evidence for ingestion of these products comes from reports of toxicity in animals and humans. Cases have been reported from outside the United States of accidental human poisoning from grains and flours contaminated with Senecio plant parts. PAs have also been detected in eggs, and honey has been shown to contain either PAs or pollen from PA-containing plants. Experimental studies of cows fed Senecio plants have demonstrated that PAs can be transmitted in milk. HUMAN CANCER STUDIES: No studies on the relationship between human cancer and exposure to riddelliine were identified. STUDIES IN EXPERIMENTAL ANIMALS: When administered by gavage, riddelliine caused significantly increased incidences of malignant and benign tumors at multiple tissue sites in B6C3F1 mice and F344/N rats. In B6C3F1 mice, exposure to riddelliine caused hemangiosarcoma in the liver in males and alveolar/bronchiolar tumors in females. In F344/N rats, exposure to riddelliine caused hemangiosarcomas in the liver in both sexes. Hepatocellular adenoma and mononuclear-cell leukemia in both sexes of rats were also considered to be treatment related. Liver nodules were observed in a small study in Wistar rats exposed to riddelliine via drinking water followed by intraperitoneal injection(s) of riddelliine. The riddelliine metabolites dehydroretronecine (R-DHP) and dehydroheliotridine (S-DHP) caused tumors in rodents exposed by dermal application, subcutaneous injection, or intraperitoneal injection. In addition, ingestion of dried plant materials or extracts containing riddelliine caused liver tumors in rats and chickens. ABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION: Riddelliine and other PAs are absorbed primarily via ingestion (though dermal absorption can occur), distributed to the liver, and excreted in the urine and feces. Riddelliine has three primary metabolic pathways: (1) hydrolysis of the ester group(s) to form the necine base, (2) oxidation of the necine base (of riddelliine) to the corresponding N-oxide (which may be reduced to riddelliine), and (3) hydroxylation of the necine base (of riddelliine), followed by dehydration to form the corresponding dehydroriddelliine (pyrrolic) derivative. This pyrrolic derivative is then hydrolyzed to form the racemic (+/-)-6,7-dihydro-7-hydroxy-1-hydroxymethyl-5H-pyrrolizine (DHP), which is a 50/50 mixture of the optically pure R-DHP and S-DHP enantiomers. Metabolism of PAs to the reactive pyrrolic ester metabolites in humans and rodents is mainly catalyzed by CYP3A and CPY2B6 isozymes of cytochrome P450. Metabolism of PAs to the corresponding N-oxides is catalyzed by both cytochrome P450- and flavin-containing monooxygenase. MECHANISMS OF GENOTOXICITY AND TUMORIGENICITY: DHP can bind DNA, which may be a key step leading to its genotoxicity and tumorigenicity. A set of eight DHP-derived adduct peaks has been detected in DNA reacted with riddelliine in the presence of rat microsomes. Dose-dependent DHP adduct formation has also been detected in livers of rats and mice exposed to riddelliine. Adduct levels were higher in endothelial cells than in parenchymal cells in rats and were more persistent in endothelial cells than in parenchymal cells in both rats and mice suggesting that tumor specificity was due to higher levels of DNA damage in the cells that form liver hemangiosarcomas. The kinetic parameters (Vmax and Km) for formation of DHP are comparable in human and rat microsomes, and the same profile of DHP-adduct peaks is also detected. In addition, other PAs have been shown to be metabolized to DHP and to cause liver tumors and, to a lesser extent, tumors of other organs, including the CNS, lung, pancreas, bladder, skin, testes, pituitary, and adrenal gland, in rats. DNA-adduct formation may play a role in the genotoxicity of riddelliine. Riddelliine induced a higher frequency of mutations in non-neoplastic endothelial cells (but not in parenchymal cells) in the cII gene mutation assay in transgenic Big Blue rats. The predominant mutations observed were G.C to T.A transversions, which are consistent with riddelliine-induced formation of DNA adducts involving G.C base pairs. Riddelliine also induced mutations in a S. typhimurium strain (TA100) that detects base-pair substitutions (in the presence of metabolic activation) but not in three other S. typhimurium strains that detect frameshift mutations (with or without metabolic activation). In addition to mutations, riddelliine also induced other types of genetic damage in mammalian experimental studies. In vitro, riddelliine increased the frequency of sister chromatid exchange and chromosomal aberrations in Chinese hamster ovary cells, cell transformation in BALB/c-3T3 fibroblast cells, and DNA cross-linking, but not DNA strand breaks in bovine kidney epithelial cells. In rats exposed in vivo, riddelliine induced S-phase synthesis in hepatocytes and endothelial cells and increased p53 expression in endothelial cells but did not induce micronucleus formation in polychromatic erythrocytes. In mice, riddelliine caused unscheduled hepatocyte DNA synthesis (in females only), but did not induce micronucleus formation. Mutations in the k-ras gene and increased p53 gene expression were detected in hemangiosarcomas from mice treated with riddelliine. In addition to the formation of exogenous (DHP-DNA adducts), the formation of endogenous DNA adducts and formation of DNA-DNA and DNA-protein cross-links have also been proposed as mechanisms of tumorigenicity. Riddelliine metabolites appear to cause damage to endothelial cells, as shown by karyomegaly and cytomegaly and accumulation of intravascular macrophages in many organs. Short-term exposure to riddelliine in rats increased apoptosis and S-phase nuclei in endothelial cells and hepatocytes. Increased levels of p53 protein were detected in endothelial cells, and vascular endothelial growth factor (VEGF), an endothelial cell-specific mitogen, was increased in hepatocytes. Development of hemangiosarcoma in the liver may have resulted from endothelial cell DNA-adduct formation, apoptosis, proliferation of endothelial cells, and mutations. Increased expression of VEGF protein also could have contributed by stimulating endothelial cell proliferation. Metabolites and analogues of riddelliine have shown carcinogenic and genotoxic properties in experimental animals. Since many of the PAs share a common metabolic activation pathway, the genotoxic and carcinogenic effects are similar to those observed with riddelliine. DHP-DNA adducts, mutations, clastogenic effects, liver tumors in rats and, to a lesser extent, tumors of other organs, including the CNS, lung, bladder, pancreas, skin, testes, pituitary, and adrenal gland, have been observed in studies with other PAs or plant extracts containing PAs. The genotoxicity, tumorigenicity, and toxicity of PAs vary, but the structure-activity relationships are not well defined. In general, the macrocyclic diester types are the most genotoxic and the monoesters types the least. While the ability of PAs to form cross-links has been proposed to affect their toxicity, only limited data are available for this potential relationship. TOXICITY: The liver is the primary target organ in humans, experimental animals, and livestock. Veno-occlusive disease is a characteristic lesion in humans poisoned by PAs. Other common effects in humans include ascites, splenomegaly, hepatomegaly, centrilobular hepatic necrosis, and cirrhosis. Young children appear to be particularly susceptible since many of the case reports involve infants and young children. Livestock poisoned by ingesting PA-containing plants often develop fatal liver disease. [The available data indicate interspecies differences in susceptibility with sheep, guinea-pigs, gerbils, hamsters, and rabbits showing resistance, while rats, cattle, horses, and chickens are highly susceptible.] The lungs are the second most common site of PA toxicity, but not all PAs affect the lungs. The primary site of damage is the pulmonary vasculature. The 11-membered macrocyclic diesters such as monocrotaline are particularly active in the lung but only at doses that were equal to or greater than doses causing liver toxicity. |
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Publication Detail:
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Type: Journal Article |
Journal Detail:
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Title: Report on carcinogens background document for [substance name] Volume: - ISSN: 2151-3805 ISO Abbreviation: Rep Carcinog Backgr Doc Publication Date: 2008 Aug |
Date Detail:
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Created Date: 2010-08-25 Completed Date: 2010-12-02 Revised Date: 2011-08-25 |
Medline Journal Info:
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Nlm Unique ID: 101519901 Medline TA: Rep Carcinog Backgr Doc Country: United States |
Other Details:
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Languages: eng Pagination: i-104 Citation Subset: IM |
Affiliation:
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U.S. Department of Health and Human Services, Public Health Services, National Toxicology Program, Research Triangle Park, NC 27709, USA. |
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| MeSH Terms | |
Descriptor/Qualifier:
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Adenoma, Liver Cell
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chemically induced Animals Carcinogens / toxicity* Cattle Chickens Cricetinae DNA Adducts Female Guinea Pigs Hemangiosarcoma / chemically induced Humans Liver / drug effects Liver Neoplasms / chemically induced Lung / drug effects Lung Diseases / chemically induced Male Mice Organ Specificity Pyrrolizidine Alkaloids / toxicity* Rabbits Rats Rats, Wistar Species Specificity |
| Chemical | |
Reg. No./Substance:
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0/Carcinogens; 0/DNA Adducts; 0/Pyrrolizidine Alkaloids; 23246-96-0/riddelliine |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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