Transepithelial Transport of 4‐Chloro‐2‐Methylphenoxyacetic Acid (MCPA) across Human Intestinal Caco‐2 Cell Monolayers

Abstract

Mechanisms of transcellular transport of 4-chloro-2-methylphenoxyacetic acid (MCPA) across the small intestine were investigated using Caco-2 cells cultured on permeable membranes. The cell monolayers were incubated with MCPA, either from apical side at pH 6.0 or 7.4, or basolateral side at pH 7.4. The accumulation and apical-to-basolateral transport of MCPA were markedly stimulated by the acidic pH on the apical side (inwardly directed H + gradient), dependent on metabolic energy and inhibited by co-incubation with acetic acid or benzoic acid. Without the H + gradient, on the other hand, the basolateral-to-apical transport of MCPA (secretory transport) was higher than the apical-to-basolateral transport (absorptive transport), although the secretory transport of MCPA was markedly lower than the absorptive transport under the H + gradient. Co-incubation of MCPA with probenecid from the basolateral side significantly inhibited the accumulation and transport of MCPA, whereas co-incubation with p-aminohippuric acid did not. These results suggest that the absorptive transport of MCPA is mediated by H + -linked monocarboxylic acid transporters expressed on the apical membranes, while secretory transport is mediated by a probenecid-sensitive transporter expressed on the basolateral membranes of Caco-2 cell monolayers.

Interactions of pesticides with membrane drug transporters: implications for toxicokinetics and toxicity

“…The handling of pesticides by SLC transporters distinct from main drug transporters, such as the L-type amino acid LAT1/2 (SLC7A5/SLC7A8) transporter or the dopamine transporter (DAT/SLC6A3), which handles glyphosate [126] or paraquat [66], respectively, also merits attention. In the same way, the molecular nature of the membrane transporters responsible for the established transepithelial transport of the herbicide 4-chloro-2-methylphenoxyacetic acid (MCPA) [127] and of the pyrethroids deltamethrin, cis-permethrin and trans-permethrin [41] across intestinal Caco-2 cells remains to be determined. The functional interplay between drug-metabolizing enzymes and transporters in pesticide absorption and disposition has additionally to be considered, as already done for drugs [128].…”