title: Oleic acid increases intestinal absorption of the BCRP/ABCG2 substrate, mitoxantrone, in mice.
abstract: The efflux transporter breast cancer resistance protein (BCRP/ABCG2) decrease intestinal absorption of many food toxicants. Oleic acid increases absorption of the specific BCRP substrate mitoxantrone (MXR), and also BCRP gene expression in human intestinal Caco-2 cells, suggesting that oleic acid affect the BCRP function. Here, we investigated the effect of oleic acid on intestinal absorption of MXR in mice. Mice were orally dosed with 2.4g oleic acid/kg b.w. and 1mg MXR/kg b.w., and sacrificed 30, 60, 90 or 120min after exposure, or were exposed to 0.6, 2.4 or 4.8g oleic acid/kg b.w. and 1mg MXR/kg b.w., and sacrificed 90min after exposure. Mice were also treated with Ko143 together with MXR and sacrificed after 60min, as a positive control of BCRP-mediated effects on MXR absorption. Absorption of MXR increased after exposure to oleic acid at all doses, and also after exposure to Ko143. Intestinal BCRP gene expression tended to increase 120min after oleic acid exposure. Our results in mice demonstrate that oleic acid decreases BCRP-mediated efflux, causing increased intestinal MXR absorption in mice. These findings may have implications in humans, concomitantly exposed to oleic acid and food contaminants that, similarly as MXR, are substrates of BCRP.
authors.affiliation: Risk and Benefit Assessment Department, National Food Agency, P.O. Box 622, SE-75126 Uppsala, Sweden. Electronic address: bitte.aspenstrom.fagerlund@slv.se.
authors.forename: Bitte
authors.initials: B
authors.lastname: Aspenström-Fagerlund
authors.affiliation: Department of Biomedical Sciences and Veterinary Public Health, Swedish University of Agricultural Sciences, Box 7028, SE-75007 Uppsala, Sweden.
authors.forename: Jonas
authors.initials: J
authors.lastname: Tallkvist
authors.affiliation: Risk and Benefit Assessment Department, National Food Agency, P.O. Box 622, SE-75126 Uppsala, Sweden; Department of Medical Sciences, Section for Infectious Diseases, Uppsala University, SE-75185 Uppsala, Sweden.
authors.forename: Nils-Gunnar
authors.initials: NG
authors.lastname: Ilbäck
authors.affiliation: Risk and Benefit Assessment Department, National Food Agency, P.O. Box 622, SE-75126 Uppsala, Sweden; Department of Environmental Toxicology, Uppsala University, Norbyvägen 18A, SE-75236 Uppsala, Sweden.
authors.forename: Anders W
authors.initials: AW
authors.lastname: Glynn
mesh_terms: D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000502:physiology*; D000818:Animals; D018938:Caco-2 Cells; D006801:Humans; D007408:Intestinal Absorption / Q000187:drug effects*; D008297:Male; D051379:Mice; D008942:Mitoxantrone / Q000493:pharmacokinetics*; D019301:Oleic Acid / Q000494:pharmacology*
chemical_list: D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; C501412:Abcg2 protein, mouse; D019301:Oleic Acid; D008942:Mitoxantrone
keywords: BCRP; FVB mice; Intestinal absorption; Mitoxantrone; Oleic acid