title: In vitro intestinal bioavailability of arsenosugar metabolites and presystemic metabolism of thio-dimethylarsinic acid in Caco-2 cells.
abstract: Whereas inorganic arsenic is classified as a human carcinogen, risks to human health related to the presence of arsenosugars in marine food are still unclear. Since studies indicate that human inorganic arsenic metabolites contribute to inorganic arsenic induced carcinogenicity, a risk assessment for arsenosugars should also include a toxicological characterization of their respective metabolites. Here we assessed intestinal bioavailability of the human arsenosugar metabolites oxo-DMAA(V), thio-DMAA(V), oxo-DMAE(V), thio-DMAE(V) and thio-DMA(V) in relation to arsenite in the Caco-2 intestinal barrier model. Whereas arsenite and thio-DMA(V) caused barrier disruption at concentrations ≥10 μM, all other metabolites did not cause a barrier leakage, even when applied at 50 times higher concentrations than arsenite and thio-DMA(V). The transfer studies point to a strong intestinal bioavailability of thio-DMA(V) and thio-DMAE(V), whereas oxo-DMAA(V), thio-DMAA(V) and oxo-DMAE(V) passed the in vitro intestinal barrier only to a very small extent. Detailed influx and efflux studies indicate that arsenite and thio-DMA(V) cross the intestinal barrier most likely by passive diffusion (paracellular) and facilitated (transcellular) transport. LC-ICP-QMS based arsenic speciation studies during the transfer experiments demonstrate transfer of thio-DMA(V) itself across the intestinal barrier and suggest metabolism of thio-DMA(V) using the in vitro intestinal barrier model to its oxygen-analogue DMA(V). In the case of arsenite no metabolism was observed. In summary the two arsenosugar metabolites thio-DMA(V) and thio-DMAE(V) showed intestinal bioavailability similar to that of arsenite, and about 10-fold higher than that reported for arsenosugars (Leffers et al., Mol. Nutr. Food Res., 2013, DOI: 10.1002/mnfr.201200821) in the same in vitro model. Thus, a presystemic metabolism of arsenosugars might strongly impact arsenic intestinal bioavailability after arsenosugar intake and should therefore be considered when assessing the risks to human health related to the consumption of arsenosugar-containing food.
authors.affiliation: Graduate School of Chemistry, University of Münster, Wilhelm-Klemm-Strasse 10, 48149 Münster, Germany.
authors.forename: Larissa
authors.initials: L
authors.lastname: Leffers
authors.forename: Christoph A
authors.initials: CA
authors.lastname: Wehe
authors.forename: Sabine
authors.initials: S
authors.lastname: Hüwel
authors.forename: Marc
authors.initials: M
authors.lastname: Bartel
authors.forename: Franziska
authors.initials: F
authors.lastname: Ebert
authors.forename: Mojtaba S
authors.initials: MS
authors.lastname: Taleshi
authors.forename: Hans-Joachim
authors.initials: HJ
authors.lastname: Galla
authors.forename: Uwe
authors.initials: U
authors.lastname: Karst
authors.forename: Kevin A
authors.initials: KA
authors.lastname: Francesconi
authors.forename: Tanja
authors.initials: T
authors.lastname: Schwerdtle
mesh_terms: D001149:Arsenates / Q000737:chemistry* / Q000493:pharmacokinetics*; D018053:Arsenites / Q000737:chemistry; D001682:Biological Availability; D018938:Caco-2 Cells; D002101:Cacodylic Acid / Q000031:analogs & derivatives* / Q000737:chemistry; D002273:Carcinogens; D002454:Cell Differentiation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002853:Chromatography, Liquid; D004058:Diffusion; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007422:Intestines / Q000187:drug effects; D009005:Monosaccharides / Q000737:chemistry* / Q000493:pharmacokinetics*; D010100:Oxygen / Q000737:chemistry; D010539:Permeability
chemical_list: D001149:Arsenates; D018053:Arsenites; D002273:Carcinogens; D009005:Monosaccharides; C449161:arsenosugar; C523062:thio-dimethylarsinate; D002101:Cacodylic Acid; C015001:arsenite; D010100:Oxygen