title: Active elimination of the marine biotoxin okadaic acid by P-glycoprotein through an in vitro gastrointestinal barrier.
abstract: The consumption of okadaic acid (OA) contaminated shellfish can induce acute toxic symptoms in humans such as diarrhea, nausea, vomiting and abdominal pain; carcinogenic and embryotoxic effects have also been described. Toxicokinetic studies with mice have shown that high cytotoxic doses of OA can pass the gastrointestinal barrier presumably by paracellular passage. However, in vitro studies using human intestinal Caco-2 cell monolayers to represent the intestinal barrier have shown that at low-dose exposure OA is transported against a concentration gradient suggesting an active efflux mechanism. Since P-glycoprotein (P-gp) transports a wide variety of substrates, we investigated its possible influence on the observed elimination of OA. We used two different cellular transwell models: (i) Caco-2 cell monolayer endogenously expressing human P-gp and simulating the intestinal barrier and (ii) MDCK-II cell monolayer stably over-expressing P-gp. Our study demonstrates clearly that OA at non-cytotoxic concentrations passes the monolayer barrier only to a low degree, and that it is actively eliminated by P-gp over the apical membrane. Therefore, our in vitro data indicate that humans appear to have efficient defense mechanisms to protect themselves against low-dose contaminated shellfish by exhibiting a low bioavailability as a result of active elimination of OA by P-gp.
authors.affiliation: Federal Institute for Risk Assessment, Department of Food Safety, Berlin, Germany. Electronic address: Anke.Ehlers@bfr.bund.de.
authors.forename: Anke
authors.initials: A
authors.lastname: Ehlers
authors.affiliation: Federal Institute for Risk Assessment, Department of Safety in the Food Chain, Berlin, Germany.
authors.forename: Anja
authors.initials: A
authors.lastname: These
authors.affiliation: Federal Institute for Risk Assessment, Department of Food Safety, Berlin, Germany.
authors.forename: Stefanie
authors.initials: S
authors.lastname: Hessel
authors.affiliation: Federal Institute for Risk Assessment, Department of Safety in the Food Chain, Berlin, Germany.
authors.forename: Angelika
authors.initials: A
authors.lastname: Preiss-Weigert
authors.affiliation: Federal Institute for Risk Assessment, Department of Food Safety, Berlin, Germany.
authors.forename: Alfonso
authors.initials: A
authors.lastname: Lampen
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism*; D000818:Animals; D001682:Biological Availability; D001692:Biological Transport; D018938:Caco-2 Cells; D002273:Carcinogens / Q000493:pharmacokinetics* / Q000633:toxicity; D002851:Chromatography, High Pressure Liquid; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008658:Inactivation, Metabolic; D007413:Intestinal Mucosa / Q000378:metabolism; D007422:Intestines / Q000187:drug effects*; D061985:Madin Darby Canine Kidney Cells; D008387:Marine Toxins / Q000493:pharmacokinetics / Q000633:toxicity; D051379:Mice; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D019319:Okadaic Acid / Q000493:pharmacokinetics* / Q000633:toxicity; D052616:Solid Phase Extraction; D053719:Tandem Mass Spectrometry
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D002273:Carcinogens; D008387:Marine Toxins; D019319:Okadaic Acid
keywords: Caco-2 model; Detoxification; MDCK-II; Marine biotoxin; Okadaic acid; P-glycoprotein