RESUMEN
We identified a reactive natural toxin, biliatresone, from Dysphania glomulifera and D. littoralis collected in Australia that produces extrahepatic biliary atresia in a zebrafish model. Three additional isoflavonoids, including the known isoflavone betavulgarin, were also isolated. Biliatresone is in the very rare 1,2-diaryl-2-propenone class of isoflavonoids. The α-methylene of the 1,2-diaryl-2-propenone of biliatresone spontaneously reacts via Michael addition in the formation of water and methanol adducts. The lethal dose of biliatresone in a zebrafish assay was 1 µg/mL, while the lethal dose of synthetic 1,2-diaryl-2-propen-1-one was 5 µg/mL, suggesting 1,2-diaryl-2-propenone as the toxic Michael acceptor.
Asunto(s)
Benzodioxoles/química , Benzodioxoles/toxicidad , Chenopodiaceae/química , Extractos Vegetales/toxicidad , Propiofenonas/química , Propiofenonas/toxicidad , Toxinas Biológicas/química , Animales , Bioensayo , Cromatografía Líquida de Alta Presión , Relación Dosis-Respuesta a Droga , Embrión no Mamífero/efectos de los fármacos , Dosificación Letal Mediana , Estructura Molecular , Pez Cebra/embriologíaRESUMEN
Biliary atresia (BA) is a rapidly progressive and destructive fibrotic disorder of unknown etiology affecting the extrahepatic biliary tree of neonates. Epidemiological studies suggest that an environmental factor, such as a virus or toxin, is the cause of the disease, although none have been definitively established. Several naturally occurring outbreaks of BA in Australian livestock have been associated with the ingestion of unusual plants by pregnant animals during drought conditions. We used a biliary secretion assay in zebrafish to isolate a previously undescribed isoflavonoid, biliatresone, from Dysphania species implicated in a recent BA outbreak. This compound caused selective destruction of the extrahepatic, but not intrahepatic, biliary system of larval zebrafish. A mutation that enhanced biliatresone toxicity mapped to a region of the zebrafish genome that has conserved synteny with an established human BA susceptibility locus. The toxin also caused loss of cilia in neonatal mouse extrahepatic cholangiocytes in culture and disrupted cell polarity and monolayer integrity in cholangiocyte spheroids. Together, these findings provide direct evidence that BA could be initiated by perinatal exposure to an environmental toxin.