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

Abstract

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.

• Authors: Lan Tang, Ye Li, Wei-Ying Chen, Shan Zeng, Ling-Na Dong, Xiao-Juan Peng, Wen Jiang, Ming Hu, Zhong-Qiu Liu
• Journal: Pharmaceutical research (Pharm Res) Vol. 31 Issue 4 Pg. 847-60 (Apr 2014) ISSN: 1573-904X [Electronic] United States
• PMID: 24092055 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• 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

Topics

• ATP Binding Cassette Transporter, Subfamily G, Member 2
• ATP-Binding Cassette Transporters (antagonists & inhibitors, physiology)
• Adenosine (analogs & derivatives, 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, physiology)
• UDP-Glucuronosyltransferase 1A9