title: Structure-activity relationship in the passage of different pyrrolizidine alkaloids through the gastrointestinal barrier: ABCB1 excretes heliotrine and echimidine.
abstract: METHODS
  1,2-Unsaturated pyrrolizidine alkaloids (PA) are found in plants such as Asteraceae and Boraginaceae families. Acute PA poisoning via contaminated food or feed causes severe damage to liver depending on species-specific oral bioavailability. For assessing PA bioavailability, their passage across the intestinal barrier was investigated using Caco-2 cells.
  
  
  METHODS
  Differentiated Caco-2 cells were exposed in transport chambers to the PA heliotrine (Hn), echimidine (Em), senecionine (Sc), and senkirkine (Sk). Cell supernatants were analyzed by LC-MS/MS.
  
  
  RESULTS
  PA pass Caco-2 monolayer from the apical into basolateral compartment depending on their chemical structure. Compared to the cyclic diesters Sc and Sk with a passage rate of 47% ± 4 and 40% ± 3, respectively, the transferred amount of the monoester Hn (32% ± 3) and open-chained diester Em (13% ± 2) was substantially lower. This suggested an active transport of Hn and Em. Using Madin-Darby canine kidney II/P-glycoprotein (ABCB1)-overexpressing cells, the active excretion of Hn and Em by ABCB1 from the gastrointestinal epithelium into the gut lumen was shown.
  
  
  CONCLUSIONS
  PA cross the intestinal barrier structure-dependently. The passage of the noncyclic PA Hn and Em is reduced by an ABCB1-driven efflux into the gastrointestinal lumen resulting in a decreased oral bioavailability.
authors.affiliation: Federal Institute for Risk Assessment (BfR), Berlin, Germany.
authors.forename: Stefanie
authors.initials: S
authors.lastname: Hessel
authors.forename: Christoph
authors.initials: C
authors.lastname: Gottschalk
authors.forename: Dania
authors.initials: D
authors.lastname: Schumann
authors.forename: Anja
authors.initials: A
authors.lastname: These
authors.forename: Angelika
authors.initials: A
authors.lastname: Preiss-Weigert
authors.forename: Alfonso
authors.initials: A
authors.lastname: Lampen
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000235:genetics / Q000378:metabolism; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D000818:Animals; D019659:Asteraceae / Q000737:chemistry; D001682:Biological Availability; D001692:Biological Transport / Q000187:drug effects; D001693:Biological Transport, Active / Q000187:drug effects; D018938:Caco-2 Cells; D002853:Chromatography, Liquid; D004285:Dogs; D041981:Gastrointestinal Tract / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D061985:Madin Darby Canine Kidney Cells; D010936:Plant Extracts / Q000737:chemistry* / Q000494:pharmacology; D011763:Pyrrolizidine Alkaloids / Q000737:chemistry* / Q000494:pharmacology; D013329:Structure-Activity Relationship; D053719:Tandem Mass Spectrometry
chemical_list: C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D010936:Plant Extracts; D011763:Pyrrolizidine Alkaloids; C009237:senecionine; C009238:senkirkine; C010178:heliotrine
keywords: ABCB1; Bioavailability; Caco-2 cell line; Hepatotoxicity; Pyrrolizidine alkaloids