title: Evaluation of intestinal absorption enhancement and local mucosal toxicity of two promoters. I. Studies in isolated rat and human colonic mucosae.
abstract: The effects of two absorption promoters, (sodium caprate (C(10)) and melittin), on intestinal permeability and viability were measured in intact rat and human colonic epithelia mounted in Ussing chambers. Apical-side addition of C(10) (10 mM) and melittin (10-50 microM) rapidly reduced the transepithelial electrical resistance (TEER) and increased the apparent permeability coefficient (Papp) of [(14)C]-mannitol and FITC-dextran-4 kDa (FD4) across colonic mucosae from both species. Effects of C(10) on flux were greater than those of melittin at the concentrations selected. C(10) irreversibly decreased TEER, but the effects of melittin were partially reversible. Enhanced permeability of polar sugars (0.18-70 kDa) in colonic mucosae with C(10) was accompanied by significant release of lactate dehydrogenase (LDH) from the luminal surface as well as by inhibition of electrogenic chloride secretion induced by the muscarinic agonist, carbachol (0.1-10 microM). Although melittin did not alter electrogenic chloride secretion in rat or human colonic mucosae, it caused leakage of LDH from rat tissue. Gross histology and electron microscopy of rat and human colonic mucosae demonstrated that each permeation enhancer can induce colonic epithelial damage at concentrations required to increase marker fluxes. C(10) led to more significant mucosal damage than melittin, characterised by sloughing and mucosal erosion. Overall, these results indicate that while C(10) and melittin increase transport of paracellular flux markers across isolated human and rat colonic mucosae in vitro, these effects are associated with some cytotoxicity.
authors.affiliation: UCD School of Agriculture, Food Science and Veterinary Medicine and UCD Conway Institute, University College Dublin, Belfield, Dublin 4, Ireland.
authors.forename: Sam
authors.initials: S
authors.lastname: Maher
authors.forename: Rory
authors.initials: R
authors.lastname: Kennelly
authors.forename: Victoria A
authors.initials: VA
authors.lastname: Bzik
authors.forename: Alan W
authors.initials: AW
authors.lastname: Baird
authors.forename: Xuexuan
authors.initials: X
authors.lastname: Wang
authors.forename: Desmond
authors.initials: D
authors.lastname: Winter
authors.forename: David J
authors.initials: DJ
authors.lastname: Brayden
mesh_terms: D000818:Animals; D018938:Caco-2 Cells; D003106:Colon / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D003652:Decanoic Acids / Q000378:metabolism / Q000633:toxicity*; D006801:Humans; D066298:In Vitro Techniques; D007408:Intestinal Absorption / Q000187:drug effects* / Q000502:physiology; D007413:Intestinal Mucosa / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism*; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008297:Male; D008555:Melitten / Q000378:metabolism / Q000633:toxicity*; D010539:Permeability / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar
chemical_list: D003652:Decanoic Acids; D008555:Melitten; C031071:decanoic acid; D007770:L-Lactate Dehydrogenase