Inhibitory effect of flavonoids on the efflux of N-acetyl 5-aminosalicylic acid intracellularly formed in Caco-2 cells.
N-acetyl 5-aminosalicylic acid (5-AcASA) that was intracellularly formed from 5-aminosalicylic acid (5-ASA) at 200 microM was discharged 5.3, 7.1, and 8.1-fold higher into the apical site than into the basolateral site during 1, 2, and 4-hour incubations, respectively, in Caco-2 cells grown in Transwells. The addition of flavonols (100 microM) such as fisetin and quercetin with 5-ASA remarkably decreased the apically directed efflux of 5-AcASA. When 5-ASA (200 microM) was added to Caco-2 cells grown in tissue culture dishes, the formation of 5-AcASA decreased, and, in addition, the formed 5-AcASA was found to be accumulated within the cells in the presence of such flavonols. Thus, the decrease in 5-AcASA efflux by such flavonols was attributed not only to the inhibition of N-acetyl-conjugation of 5-ASA but to the predominant cellular accumulation of 5-AcASA. Various flavonoids also had both of the effects with potencies that depend on their specific structures. The essential structure of flavonoids was an absence of a hydroxyl substitution at the C5 position on the A-ring of flavone structure for the inhibitory effect on the N-acetyl-conjugation of 5-ASA, and a presence of hydroxyl substitutions at the C3' or C4' position on the B-ring of flavone structure for the promoting effect on the cellular accumulation of 5-AcASA. Both the decrease in 5-AcASA apical efflux and the increase in 5-AcASA cellular accumulation were also caused by MK571 and indomethacin, inhibitors of MRPs, but not by quinidine, cyclosporin A, P-glycoprotein inhibitors, and mitoxantrone, a BCRP substrate. These results suggest that certain flavonoids suppress the apical efflux of 5-AcASA possibly by inhibiting MRPs pumps located on apical membranes in Caco-2 cells.
Yoshimura
Shin
S
Faculty of Pharmacy and Pharmaceutical Sciences, Fukuyama University, Sanzou, Gakuen-cho, Fukuyama, Hiroshima 729-0292, Japan.
Kawano
Kentaro
K
Matsumura
Ryusuke
R
Sugihara
Narumi
N
Furuno
Koji
K
D000636:Aminosalicylic Acids / Q000493:pharmacokinetics*; D001692:Biological Transport / Q000187:drug effects; D018938:Caco-2 Cells; D045744:Cell Line, Tumor; D003470:Culture Media; D004347:Drug Interactions; D005419:Flavonoids / Q000494:pharmacology*; D006801:Humans; D019804:Mesalamine / Q000493:pharmacokinetics; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism
D000636:Aminosalicylic Acids; D003470:Culture Media; D005419:Flavonoids; D019804:Mesalamine; D027425:ATP-Binding Cassette, Sub-Family C Proteins; C028836:N-acetyl-5-aminosalicylic acid
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