Genotoxic Pyrrolizidine Alkaloids — Mechanisms Leading to DNA Adduct Formation and Tumorigenicity
نویسندگان
چکیده
Plants that contain pyrrolizidine alkaloids are widely distributed in the world. Although pyrrolizidine alkaloids have been shown to be genotoxic and tumorigenic in experimental animals, the mechanisms of actions have not been fully understood. The results of our recent mechanistic studies suggest that pyrrolizidine alkaloids induce tumors via a genotoxic mechanism mediated by 6,7-dihydro-7-hydroxy-1-hydroxymethyl-5Hpyrrolizine (DHP)-derived DNA adduct formation. This mechanism may be general to most carcinogenic pyrrolizidine alkaloids, including the retronecine-, heliotridine-, and otonecinetype pyrrolizidine alkaloids. It is hypothesized that these DHP-derived DNA adducts are potential biomarkers of pyrrolizidine alkaloid tumorigenicity. The mechanisms that involve the formation of DNA cross-linking and endogenous DNA adducts are also discussed.
منابع مشابه
Metabolic Activation of the Tumorigenic Pyrrolizidine Alkaloid, Retrorsine, Leading to DNA Adduct Formation In Vivo
Pyrrolizidine alkaloids are naturally occurring genotoxic chemicals produced by a large number of plants. The high toxicity of many pyrrolizidine alkaloids has caused considerable loss of free-ranging livestock due to liver and pulmonary lesions. Chronic exposure of toxic pyrrolizidine alkaloids to laboratory animals induces cancer. This investigation studies the metabolic activation of retrors...
متن کاملGenotoxicity of a variety of pyrrolizidine alkaloids in the hepatocyte primary culture-DNA repair test using rat, mouse, and hamster hepatocytes.
Seventeen pyrrolizidine alkaloids were studied with the hepatocyte primary culture-DNA repair test using rat hepatocytes. DNA repair synthesis was elicited by 15 alkaloids, including 11 of unknown carcinogenicity, i.e., senecionine, seneciphylline, jacobine, epoxyseneciphylline, senecicannabine, acetylfukinotoxin, syneilesine, dihydroclivorine, ligularidine, neoligularidine, and ligularizine. T...
متن کاملPyrrolizidine alkaloids from Heliotropium transoxanum Bunge
Background and objectives: The plants belonging to the genus Heliotropium L. (Boraginaceae) are the main sources of toxic pyrrolizidine alkaloids (PAs). In the present study, we have investigated the PAs of the aerial parts of Heliotropium transoxanum Bunge, a perennial species native to Iran. Methods: Silica gel column chromatography and silica gel PTLC were applied ...
متن کاملFormation of cyclic adducts of deoxyguanosine with the aldehydes trans-4-hydroxy-2-hexenal and trans-4-hydroxy-2-nonenal in vitro.
trans-4-Hydroxy-2-hexenal (t-4HH), a reactive metabolite isolated from the pyrrolizidine alkaloid senecionine, and trans-4-hydroxy-2-nonenal (t-4HN), a product of lipid peroxidation, reacted nonenzymatically with deoxyguanosine at pH 7.4 at 37 degrees C in vitro with each compound yielding two pairs of diastereomeric adducts. Adducts were isolated using reverse phase high-performance liquid chr...
متن کاملCarry-over of pyrrolizidine alkaloids from feed to milk in dairy cows.
Pyrrolizidine alkaloids are toxins present in many plants belonging to the families of Asteraceae, Boraginaceae and Fabaceae. Particularly notorious are pyrrolizidine alkaloids present in ragwort species (Senecio), which are held responsible for hepatic disease in horses and cows and may lead to the death of the affected animals. In addition, these compounds may be transferred to edible product...
متن کامل