title: Inhibitory effect of flavonoids on the efflux of N-acetyl 5-aminosalicylic acid intracellularly formed in Caco-2 cells.
abstract: 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.
authors.affiliation: Faculty of Pharmacy and Pharmaceutical Sciences, Fukuyama University, Sanzou, Gakuen-cho, Fukuyama, Hiroshima 729-0292, Japan.
authors.forename: Shin
authors.initials: S
authors.lastname: Yoshimura
authors.forename: Kentaro
authors.initials: K
authors.lastname: Kawano
authors.forename: Ryusuke
authors.initials: R
authors.lastname: Matsumura
authors.forename: Narumi
authors.initials: N
authors.lastname: Sugihara
authors.forename: Koji
authors.initials: K
authors.lastname: Furuno
mesh_terms: 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
chemical_list: D000636:Aminosalicylic Acids; D003470:Culture Media; D005419:Flavonoids; D019804:Mesalamine; D027425:ATP-Binding Cassette, Sub-Family C Proteins; C028836:N-acetyl-5-aminosalicylic acid
references.citation: Biochem Pharmacol. 1983 Apr 1;32(7):1141-8
references.pmid: 6342623
references.citation: Oncol Res. 2003;13(11):463-9
references.pmid: 12812360
references.citation: Cancer Res. 1996 Mar 1;56(5):988-94
references.pmid: 8640791
references.citation: J Pharmacol Exp Ther. 2000 Jan;292(1):433-9
references.pmid: 10604980
references.citation: Biochem Pharmacol. 2005 Jun 1;69(11):1657-65
references.pmid: 15896345
references.citation: Cell Mol Life Sci. 2002 Feb;59(2):307-22
references.pmid: 11915946
references.citation: Biochem Pharmacol. 2005 Feb 15;69(4):699-708
references.pmid: 15670588
references.citation: Pharmacol Toxicol. 1997;81 Suppl 2:1-28
references.pmid: 9396082
references.citation: Biochem Biophys Res Commun. 2003 Oct 10;310(1):222-7
references.pmid: 14511674
references.citation: Drug Metab Dispos. 2003 Sep;31(9):1176-86
references.pmid: 12920174
references.citation: Gut. 1983 Mar;24(3):213-7
references.pmid: 6131017
references.citation: J Pharmacol Exp Ther. 2003 Mar;304(3):1258-67
references.pmid: 12604704
references.citation: Acta Pol Pharm. 2004 Dec;61 Suppl:8-10
references.pmid: 15909923
references.citation: Gastroenterology. 1978 Oct;75(4):638-40
references.pmid: 30669
references.citation: Br J Pharmacol. 2004 Dec;143(7):856-64
references.pmid: 15504753
references.citation: N Engl J Med. 1973 Sep 6;289(10):491-5
references.pmid: 4146729
references.citation: Cancer Lett. 2006 Mar 8;234(1):73-80
references.pmid: 16303243
references.citation: Jpn J Exp Med. 1983 Feb;53(1):41-50
references.pmid: 6876476
references.citation: Drug Metab Dispos. 1999 Apr;27(4):479-85
references.pmid: 10101143
references.citation: J Pharmacol Exp Ther. 2006 Oct;319(1):459-67
references.pmid: 16857726
references.citation: Eur J Clin Pharmacol. 1975 Dec 19;9(2-3):229-34
references.pmid: 1233267
references.citation: Gastroenterology. 1989 Jul;97(1):38-41
references.pmid: 2566551
references.citation: Cancer Chemother Pharmacol. 2006 Oct;58(4):494-503
references.pmid: 16437251
references.citation: Biol Pharm Bull. 2004 Sep;27(9):1455-8
references.pmid: 15340238
references.citation: Scand J Gastroenterol. 1980;15(6):715-9
references.pmid: 7010522
references.citation: Gastroenterology. 1995 May;108(5):1427-33
references.pmid: 7729635
references.citation: Adv Drug Deliv Rev. 2002 Nov 18;54(10):1311-31
references.pmid: 12406647
references.citation: Toxicology. 2006 Jun 1;223(1-2):156-65
references.pmid: 16647797
references.citation: J Chromatogr. 1987 Jan 9;385:299-304
references.pmid: 3558586
references.citation: Mol Pharmacol. 2001 May;59(5):1171-80
references.pmid: 11306701
references.citation: Arch Biochem Biophys. 2005 Jan 15;433(2):428-34
references.pmid: 15581599
references.citation: Drug Saf. 2002;25(8):561-82
references.pmid: 12113642
references.citation: Biochem Pharmacol. 2007 Jul 15;74(2):345-51
references.pmid: 17509533
references.citation: Biochim Biophys Acta. 1999 Dec 6;1461(2):377-94
references.pmid: 10581368
references.citation: J Pharmacol Exp Ther. 2000 Sep;294(3):830-6
references.pmid: 10945830
references.citation: Arch Toxicol. 2006 May;80(5):243-9
references.pmid: 16244858
references.citation: Pharmacol Ther. 2006 Jan;109(1-2):137-61
references.pmid: 16209890
references.citation: Am J Gastroenterol. 2002 Jul;97(7):1763-8
references.pmid: 12135032