Breast cancer resistance protein-mediated efflux of luteolin glucuronides in HeLa cells overexpressing UDP-glucuronosyltransferase 1A9

Pharm Res. 2014 Apr;31(4):847-60. doi: 10.1007/s11095-013-1207-0. Epub 2013 Oct 3.


Purpose: UDP-glucuronosyltransferases (UGTs) are responsible for the formation of glucuronides of polyphenolic flavonoids. This study investigated the UGT1A9-mediated glucuronidation of luteolin and the kinetics of luteolin glucuronide efflux.

Method: HeLa cells overexpressing UGT1A9 (HeLa-UGT1A9) were used to determine the kinetics of breast cancer resistance protein (BCRP)-mediated transport of luteolin glucuronides. Human UGT isoforms were used to determine glucuronidation rates.

Results: UGT1A9 was found to catalyze the production of four luteolin glucuronides, including three known monoglucuronides and a novel 3', 4'-diglucuronide. Ko143, a potent specific inhibitor of BCRP, significantly inhibited efflux of luteolin monoglucuronides from HeLa1A9 cells and increased their intracellular levels in a dose-dependent manner. The formation of luteolin diglucuronide was observed when intracellular concentration of total monoglucuronides went above 0.07 nM.

Conclusions: Intracellular accumulation of diglucuronide was detected at high monoglucuronide concentrations (>0.07 nM). Diglucuronide production is speculated to be a compensatory pathway for luteolin disposition.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily G, Member 2
  • ATP-Binding Cassette Transporters / antagonists & inhibitors
  • ATP-Binding Cassette Transporters / physiology*
  • Adenosine / analogs & derivatives
  • Adenosine / pharmacology
  • Breast Neoplasms / metabolism*
  • Diketopiperazines
  • Dose-Response Relationship, Drug
  • Female
  • Glucuronides / metabolism*
  • Glucuronosyltransferase / biosynthesis*
  • HeLa Cells
  • Heterocyclic Compounds, 4 or More Rings
  • Humans
  • Luteolin / metabolism*
  • Neoplasm Proteins / antagonists & inhibitors
  • Neoplasm Proteins / physiology*
  • UDP-Glucuronosyltransferase 1A9


  • 3-(6-isobutyl-9-methoxy-1,4-dioxo-1,2,3,4,6,7,12,12a-octahydropyrazino(1',2'-1,6)pyrido(3,4-b)indol-3-yl)propionic acid tert-butyl ester
  • ABCG2 protein, human
  • ATP Binding Cassette Transporter, Subfamily G, Member 2
  • ATP-Binding Cassette Transporters
  • Diketopiperazines
  • Glucuronides
  • Heterocyclic Compounds, 4 or More Rings
  • Neoplasm Proteins
  • UGT1A9 protein, human
  • Glucuronosyltransferase
  • UDP-Glucuronosyltransferase 1A9
  • Adenosine
  • Luteolin