Home About Browse Search
Svenska


Dietary fatty acids increase the absorption of toxic substances and drugs by modifying different absorption pathways in the intestinal epithelium

Aspenström-Fagerlund, Bitte (2012). Dietary fatty acids increase the absorption of toxic substances and drugs by modifying different absorption pathways in the intestinal epithelium. Diss. (sammanfattning/summary) Uppsala : Sveriges lantbruksuniv., Acta Universitatis agriculturae Sueciae, 1652-6880 ; 2012:88
ISBN 978-91-576-7735-8
[Doctoral thesis]

[img]
Preview
PDF
2MB

Abstract

Dietary fatty acids have surface active properties comparable to substances used as absorption enhancers of poorly absorbed drugs. The intestinal epithelium serves as a gatekeeping barrier for the absorption of toxic substances, nutrients and drugs. In this thesis it is hypothesized that dietary fat might compromise this barrier function of the intestinal epithelium. Different absorption pathways in the intestinal epithelium, i.e. the paracellular pathway regulated by tight junctions, and the restriction of the active transcellular pathway by the efflux transporter breast cancer resistance protein (BCRP/ABCG2) were studied. Mannitol and mitoxantrone (MXR) were used as marker substances for the respective pathway. Physiologically relevant doses for humans of the important dietary fatty acids docosahexaenoic acid (DHA) and oleic acid were used. Absorption of cadmium (Cd) and aluminium (Al), relevant in a food contaminant perspective, was investigated.

DHA caused a significantly increased apical to basolateral absorption of mannitol, Cd and Al through Caco-2 cell monolayers. Moreover, oleic acid increased absorption of mannitol and Al, but not of Cd. As mannitol is a marker for paracellular absorption the findings confirm that oleic acid and DHA increase absorption of poorly absorbed substances through the paracellular pathway in Caco-2 cell monolayers. Morphological analyses with fluorescence microscopy and transmission electron microscopy supported these findings.

Oleic acid increased absorption of MXR both in Caco-2 cell monolayers and in mice. In mice, the levels of MXR were increased in blood, intestine, kidney, brain and liver.
Oleic acid also caused an up-regulation of BCRP gene expression in Caco-2 cells. These findings suggest that oleic acid decrease the function of the BCRP mediated- efflux of MXR.

Overall, the results in this thesis have important toxico-kinetic implications for many food toxicants normally restricted to be absorbed through the paracellular pathway or effluxed by BCRP. The fact that dietary fatty acids increased oral absorption of toxic substances is an important finding that ought to be considered in future risk assessment. Consequently, risk-based limits for toxic substances may be underestimated if they are established in animal studies using diets with low fat content.

Authors/Creators:Aspenström-Fagerlund, Bitte
Title:Dietary fatty acids increase the absorption of toxic substances and drugs by modifying different absorption pathways in the intestinal epithelium
Series/Journal:Acta Universitatis agriculturae Sueciae (1652-6880)
Year of publishing :9 November 2012
Volume:2012:88
Number of Pages:88
Papers/manuscripts:
NumberReferences
I.Aspenström-Fagerlund B., Ring L., Aspenström P., Tallkvist J., Ilbäck NG., Glynn A.W., (2007). Oleic acid and docosahexaenoic acid cause an inrease in the paracellular absorption of hydrophilic compounds in an experimental model of human absorptive enterocytes. Toxicology 237, 12 - 23.
II.Aspenström-Fagerlund B., Sundström B., Tallkvist J., Ilbäck N-G., Glynn A.W., (2009). Fatty acids increase paracellular absorption of aluminium across Caco-2 cell monolayers. Chemico-Biological Interactions 181, 272- 278.
III.Aspenström-Fagerlund B., Tallkvist J., Ilbäck N-G., Glynn A.W., (2012). Oleic acid decreases BCRP mediated efflux of mitoxantrone in Caco-2 cell monolayers. Food and Chemical Toxicology (2012) 50, 3635-3645.
IV.Aspenström-Fagerlund B., Tallkvist J., Ilbäck N-G., Glynn A.W. (2012) Oleic acid decreases BCRP mediated efflux of mitoxantrone in mice (in manuscript).
Place of Publication:Uppsala
Publisher:Dept. of Biomedical Sciences and Veterinary Public Health, Swedish University of Agricultural Sciences
ISBN for printed version:978-91-576-7735-8
ISSN:1652-6880
Language:English
Publication Type:Doctoral thesis
Full Text Status:Public
Agris subject categories.:L Animal production > L51 Animal physiology - Nutrition
Q Food science > Q03 Food contamination and toxicology
S Human nutrition > S20 Physiology of human nutrition
Subjects:(A) Swedish standard research categories 2011 > 3 Medical and Health Sciences > 301 Basic Medicine > Pharmacology and Toxicology
(A) Swedish standard research categories 2011 > 4 Agricultural Sciences > 403 Veterinary Science > Medical Bioscience
Agrovoc terms:oleic acid, docosahexaenoic acid, lipids, nutrients, toxic substances, cadmium, aluminium, mannitol, absorption, epithelium, mice, laboratory animals, in vitro experimentation
Keywords:oleic acid, DHA, mannitol, cadmium, aluminium, mitoxantrone, BCRP, tight junctions, Caco-2 cells, FVB mice
URN:NBN:urn:nbn:se:slu:epsilon-e-714
Permanent URL:
http://urn.kb.se/resolve?urn=urn:nbn:se:slu:epsilon-e-714
ID Code:9226
Department:(VH) > Dept. of Biomedical Sciences and Veterinary Public Health
Deposited By: MSc Bitte Aspenström-Fagerlund
Deposited On:09 Nov 2012 07:55
Metadata Last Modified:02 Dec 2014 10:53

Repository Staff Only: item control page

Downloads

Downloads per year (since September 2012)

View more statistics

Downloads
Hits