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

Sammanfattning: 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.