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• W1601648992 abstract "The ATP-Binding Cassette (ABC) of transmembrane proteins comprises a large superfamily of efflux transporters with diverse physiological functions. Three members, ABCB1, ABCC2 and ABCG2, are predominantly expressed at the luminal membranes of excretory organs like the liver and the kidneys, as well as at biological barriers, as for example the intestinal barrier and the blood-brain barrier. It has been postulated that not only many drugs but also various toxins are substrates for these transporters, which in turn represent an innate defence mechanism of the organism against many undesirable food/feed components as well as toxins. In the first part of the thesis, three different substances were studied in a defined cell culture model comprising Caco-2 cells that resemble the intestinal barrier and allow the prediction of drug/toxin absorption and passage into barrier-protected tissues. Three compounds, that are relevant to pigs were selected: the antibiotic oxytetracycline was chosen due to its long-standing and common use in pig health care, despite its low oral bioavailability. In contrast, danofloxacin, a modern fluoroquinolone was selected as it gains importance in the therapy of infectious diseases in pigs. The third compound, the mycotoxin ochratoxin A, was included in these tests as it is known that pigs are the most sensitive animal species, and hence insight into the organ distribution of the toxin might contribute to the understanding of this species-specific sensitivity. All three compounds were found to be substrates for one or more ABC transporters and hence these findings confirmed that more detailed information on the tissue distribution of ABC transporters, particularly ABCB1, ABCC2 and ABCG2 in pigs, is needed. Subsequently the expression of P-gp (ABCB1), MRP2 (ABCC2) and BCRP (ABCG2) was investigated by immunohistochemistry and quantitative RT- PCR analysis in a wide range of porcine tissues. A comparison of these findings with investigations in other species indicated a lower level of expression of P-gp in porcine kidneys and BCRP in porcine liver, as compared to human and rodent data. These findings suggest that the differences in the kinetics of the mentioned therapeutics and the mycotoxin are partly attributable to species-differences at the level of membrane transporters. Sequence analysis of porcine transporters demonstrated a high degree of homology with the corresponding human ABC proteins, which was higher than that for mice and rats. These findings confirm the good correlation between the kinetic data obtained from humans and pigs, and suggest that bioassays in pigs or with pig tissues may serve as an elegant model for kinetic studies with drugs and toxins affecting humans. Finally, an easy and rapid model, based on isolated porcine lymphocytes is presented, that allows to predict directly the function of P-gp. These functional studies quantify P-gp dependent Rhodamin 123 transport and allow to identify not only substrates but also inhibitors of P-gp. The latter might be involved in drug-drug interactions and interactions between drugs, toxins and dietary components. In conclusion, the presented results provide for the first time detailed insight into the levels of expression and function of ABC transporters in pigs." @default.
• W1601648992 created "2016-06-24" @default.
• W1601648992 creator A5005683004 @default.
• W1601648992 date "2006-10-23" @default.
• W1601648992 modified "2023-09-27" @default.
• W1601648992 title "ABC-transporters in the pig" @default.
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